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    Carbonic anhydrase XII functions in health and disease. Waheed Abdul,Sly William S Gene Human CAXII was initially identified as a cancer marker in different cancers and tumors. Expression of CAXII is regulated by hypoxia and estrogen receptors. CAXII expression has been also detected in several tissues, whereas in cancer and tumor tissues its expression is several fold higher. In brain tumors, an alternatively spliced form of CAXII is expressed. Higher expression of CAXII in breast cancer is indicative of lower grade disease. CAXII plays a key role in several physiological functions. Mutation in the CAXII gene causes cystic fibrosis-like syndrome and salt wasting disease. CAXII is also seen in nuclear pulposus cells of the vertebrae. Aging dependent stiffness or degeneration of backbone correlates with CAXII expression level. This finding suggests a possible implication of CAXII as a biomarker for chronic back pain and a pharmacological target for possible treatment of chronic back pain. 10.1016/j.gene.2017.04.027
    BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation. Li Andrew G,Murphy Elizabeth C,Culhane Aedin C,Powell Emily,Wang Hua,Bronson Roderick T,Von Thanh,Giobbie-Hurder Anita,Gelman Rebecca S,Briggs Kimberly J,Piwnica-Worms Helen,Zhao Jean J,Kung Andrew L,Kaelin William G,Livingston David M Proceedings of the National Academy of Sciences of the United States of America is an established breast and ovarian tumor suppressor gene that encodes multiple protein products whose individual contributions to human cancer suppression are poorly understood. BRCA1-IRIS (also known as "IRIS"), an alternatively spliced product and a chromatin-bound replication and transcription regulator, is overexpressed in various primary human cancers, including breast cancer, lung cancer, acute myeloid leukemia, and certain other carcinomas. Its naturally occurring overexpression can promote the metastasis of patient-derived xenograft (PDX) cells and other human cancer cells in mouse models. The IRIS-driven metastatic mechanism results from IRIS-dependent suppression of phosphatase and tensin homolog () transcription, which in turn perturbs the PI3K/AKT/GSK-3β pathway leading to prolyl hydroxylase-independent HIF-1α stabilization and activation in a normoxic environment. Thus, despite the tumor-suppressing genetic origin of IRIS, its properties more closely resemble those of an oncoprotein that, when spontaneously overexpressed, can, paradoxically, drive human tumor progression. 10.1073/pnas.1807112115
    Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Tian Lin,Goldstein Amit,Wang Hai,Ching Lo Hin,Sun Kim Ik,Welte Thomas,Sheng Kuanwei,Dobrolecki Lacey E,Zhang Xiaomei,Putluri Nagireddy,Phung Thuy L,Mani Sendurai A,Stossi Fabio,Sreekumar Arun,Mancini Michael A,Decker William K,Zong Chenghang,Lewis Michael T,Zhang Xiang H-F Nature Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis. This paradox may be resolved by vessel normalization, which involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia. Although these processes alter tumour progression, their regulation is poorly understood. Here we show that type 1 T helper (T1) cells play a crucial role in vessel normalization. Bioinformatic analyses revealed that gene expression features related to vessel normalization correlate with immunostimulatory pathways, especially T lymphocyte infiltration or activity. To delineate the causal relationship, we used various mouse models with vessel normalization or T lymphocyte deficiencies. Although disruption of vessel normalization reduced T lymphocyte infiltration as expected, reciprocal depletion or inactivation of CD4 T lymphocytes decreased vessel normalization, indicating a mutually regulatory loop. In addition, activation of CD4 T lymphocytes by immune checkpoint blockade increased vessel normalization. T1 cells that secrete interferon-γ are a major population of cells associated with vessel normalization. Patient-derived xenograft tumours growing in immunodeficient mice exhibited enhanced hypoxia compared to the original tumours in immunocompetent humans, and hypoxia was reduced by adoptive T1 transfer. Our findings elucidate an unexpected role of T1 cells in vasculature and immune reprogramming. T1 cells may be a marker and a determinant of both immune checkpoint blockade and anti-angiogenesis efficacy. 10.1038/nature21724
    UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α. Goto Yoko,Zeng Lihua,Yeom Chan Joo,Zhu Yuxi,Morinibu Akiyo,Shinomiya Kazumi,Kobayashi Minoru,Hirota Kiichi,Itasaka Satoshi,Yoshimura Michio,Tanimoto Keiji,Torii Masae,Sowa Terumasa,Menju Toshi,Sonobe Makoto,Kakeya Hideaki,Toi Masakazu,Date Hiroshi,Hammond Ester M,Hiraoka Masahiro,Harada Hiroshi Nature communications Hypoxia-inducible factor 1 (HIF-1) plays a role in tumour metastases; however, the genes that activate HIF-1 and subsequently promote metastases have yet to be identified. Here we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1) abrogates the von Hippel-Lindau-mediated ubiquitination of HIF-1α, the regulatory subunit of HIF-1, and consequently promotes metastasis. The aberrant overexpression of UCHL1 facilitates distant tumour metastases in a HIF-1-dependent manner in murine models of pulmonary metastasis. Meanwhile, blockade of the UCHL1-HIF-1 axis suppresses the formation of metastatic tumours. The expression levels of UCHL1 correlate with those of HIF-1α and are strongly associated with the poor prognosis of breast and lung cancer patients. These results indicate that UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1α, which justifies exploiting it as a prognostic marker and therapeutic target of cancers. 10.1038/ncomms7153
    Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Blandino Giovanni,Valerio Mariacristina,Cioce Mario,Mori Federica,Casadei Luca,Pulito Claudio,Sacconi Andrea,Biagioni Francesca,Cortese Giancarlo,Galanti Sergio,Manetti Cesare,Citro Gennaro,Muti Paola,Strano Sabrina Nature communications Diabetic patients treated with metformin have a reduced incidence of cancer and cancer-related mortality. Here we show that metformin affects engraftment and growth of breast cancer tumours in mice. This correlates with the induction of metabolic changes compatible with clear anticancer effects. We demonstrate that microRNA modulation underlies the anticancer metabolic actions of metformin. In fact, metformin induces DICER expression and its effects are severely impaired in DICER knocked down cells. Conversely, ectopic expression of DICER recapitulates the effects of metformin in vivo and in vitro. The microRNAs upregulated by metformin belong mainly to energy metabolism pathways. Among the messenger RNAs downregulated by metformin, we found c-MYC, IRS-2 and HIF1alpha. Downregulation of c-MYC requires AMP-activated protein kinase-signalling and mir33a upregulation by metformin. Ectopic expression of c-MYC attenuates the anticancer metabolic effects of metformin. We suggest that DICER modulation, mir33a upregulation and c-MYC targeting have an important role in the anticancer metabolic effects of metformin. 10.1038/ncomms1859
    Int6/eIF3e silencing promotes functional blood vessel outgrowth and enhances wound healing by upregulating hypoxia-induced factor 2alpha expression. Chen Li,Endler Alexander,Uchida Kazuyo,Horiguchi Shin-ichiro,Morizane Yoshihito,Iijima Osamu,Toi Masakazu,Shibasaki Futoshi Circulation BACKGROUND:We previously identified INT6/eIF3e as a novel regulator of hypoxia-inducible factor 2alpha (HIF2alpha) activity. Small interfering RNA (siRNA)-Int6 adequately stabilized HIF2alpha, even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo. METHODS AND RESULTS:We demonstrated a 6- to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure of the injury. HIF2alpha accumulation caused by siRNA-Int6 was confirmed as the unequivocal cause of the angiogenesis by an in vivo angiogenesis assay. Further analysis of the Int6 silencing-induced neoangiogenesis revealed that a negative feedback regulation of HIF2alpha stability was caused by HIF2alpha-induced transcription of Int6 via hypoxia-response elements in its promoter. Thus, siRNA-Int6 temporarily facilitates an accumulation of HIF2alpha protein, leading to hypoxia-independent transcription of angiogenic factors and concomitant neoangiogenesis. CONCLUSIONS:We suggest that the pathway involving INT6/HIF2alpha acts as a hypoxia-independent master switch of functional angiogenesis; therefore, siRNA-Int6 application might be of clinical value in treating ischemic diseases such as heart and brain ischemia, skin injury, and diseases involving obstructed vessels. 10.1161/CIRCULATIONAHA.109.931931
    SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Finley Lydia W S,Carracedo Arkaitz,Lee Jaewon,Souza Amanda,Egia Ainara,Zhang Jiangwen,Teruya-Feldstein Julie,Moreira Paula I,Cardoso Sandra M,Clish Clary B,Pandolfi Pier Paolo,Haigis Marcia C Cancer cell Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression. 10.1016/j.ccr.2011.02.014
    Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides. Hulea Laura,Gravel Simon-Pierre,Morita Masahiro,Cargnello Marie,Uchenunu Oro,Im Young Kyuen,Lehuédé Camille,Ma Eric H,Leibovitch Matthew,McLaughlan Shannon,Blouin Marie-José,Parisotto Maxime,Papavasiliou Vasilios,Lavoie Cynthia,Larsson Ola,Ohh Michael,Ferreira Tiago,Greenwood Celia,Bridon Gaëlle,Avizonis Daina,Ferbeyre Gerardo,Siegel Peter,Jones Russell G,Muller William,Ursini-Siegel Josie,St-Pierre Julie,Pollak Michael,Topisirovic Ivan Cell metabolism There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism. 10.1016/j.cmet.2018.09.001
    Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Schug Zachary T,Peck Barrie,Jones Dylan T,Zhang Qifeng,Grosskurth Shaun,Alam Israt S,Goodwin Louise M,Smethurst Elizabeth,Mason Susan,Blyth Karen,McGarry Lynn,James Daniel,Shanks Emma,Kalna Gabriela,Saunders Rebecca E,Jiang Ming,Howell Michael,Lassailly Francois,Thin May Zaw,Spencer-Dene Bradley,Stamp Gordon,van den Broek Niels J F,Mackay Gillian,Bulusu Vinay,Kamphorst Jurre J,Tardito Saverio,Strachan David,Harris Adrian L,Aboagye Eric O,Critchlow Susan E,Wakelam Michael J O,Schulze Almut,Gottlieb Eyal Cancer cell A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment. 10.1016/j.ccell.2014.12.002
    Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Favaro Elena,Bensaad Karim,Chong Mei G,Tennant Daniel A,Ferguson David J P,Snell Cameron,Steers Graham,Turley Helen,Li Ji-Liang,Günther Ulrich L,Buffa Francesca M,McIntyre Alan,Harris Adrian L Cell metabolism Metabolic reprogramming of cancer cells provides energy and multiple intermediates critical for cell growth. Hypoxia in tumors represents a hostile environment that can encourage these transformations. We report that glycogen metabolism is upregulated in tumors in vivo and in cancer cells in vitro in response to hypoxia. In vitro, hypoxia induced an early accumulation of glycogen, followed by a gradual decline. Concordantly, glycogen synthase (GYS1) showed a rapid induction, followed by a later increase of glycogen phosphorylase (PYGL). PYGL depletion and the consequent glycogen accumulation led to increased reactive oxygen species (ROS) levels that contributed to a p53-dependent induction of senescence and markedly impaired tumorigenesis in vivo. Metabolic analyses indicated that glycogen degradation by PYGL is important for the optimal function of the pentose phosphate pathway. Thus, glycogen metabolism is a key pathway induced by hypoxia, necessary for optimal glucose utilization, which represents a targetable mechanism of metabolic adaptation. 10.1016/j.cmet.2012.10.017
    Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Thienpont Bernard,Steinbacher Jessica,Zhao Hui,D'Anna Flora,Kuchnio Anna,Ploumakis Athanasios,Ghesquière Bart,Van Dyck Laurien,Boeckx Bram,Schoonjans Luc,Hermans Els,Amant Frederic,Kristensen Vessela N,Peng Koh Kian,Mazzone Massimiliano,Coleman Mathew,Carell Thomas,Carmeliet Peter,Lambrechts Diether Nature Hypermethylation of the promoters of tumour suppressor genes represses transcription of these genes, conferring growth advantages to cancer cells. How these changes arise is poorly understood. Here we show that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells. TET enzymes catalyse DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor activity or reactive oxygen species, and depends directly on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. In patients, tumour suppressor gene promoters are markedly more methylated in hypoxic tumour tissue, independent of proliferation, stromal cell infiltration and tumour characteristics. Our data suggest that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage. Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect. Tumour hypoxia therefore acts as a novel regulator of DNA methylation. 10.1038/nature19081
    Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Erler Janine T,Bennewith Kevin L,Cox Thomas R,Lang Georgina,Bird Demelza,Koong Albert,Le Quynh-Thu,Giaccia Amato J Cancer cell Tumor cell metastasis is facilitated by "premetastatic niches" formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease. 10.1016/j.ccr.2008.11.012
    Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia. Wang Yuanyuan,Bai Changsen,Ruan Yuxia,Liu Miao,Chu Qiaoyun,Qiu Li,Yang Chuanzhen,Li Binghui Nature communications Under hypoxia, most of glucose is converted to secretory lactate, which leads to the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid over-accumulating ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate, which is indispensable to glutamine-carbon metabolism under hypoxia. We found that glutamine nitrogen is necessary to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. Furthermore, we found that the specific metabolic pathway occurs in vivo and is required for tumor growth. The identified metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Therefore, our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism. 10.1038/s41467-018-08033-9
    O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Ferrer Christina M,Lynch Thomas P,Sodi Valerie L,Falcone John N,Schwab Luciana P,Peacock Danielle L,Vocadlo David J,Seagroves Tiffany N,Reginato Mauricio J Molecular cell The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation, and interaction with von Hippel-Lindau protein (pVHL), resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of endoplasmic reticulum (ER) stress and cancer cell apoptosis mediated through C/EBP homologous protein (CHOP). HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress, as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects. Human breast cancers with high levels of HIF-1α contain elevated OGT, and lower OGA levels correlate independently with poor patient outcome. Thus, O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α. 10.1016/j.molcel.2014.04.026
    The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression. Ma Biao,Cheng Hongcheng,Mu Chenglong,Geng Guangfeng,Zhao Tian,Luo Qian,Ma Kaili,Chang Rui,Liu Qiangqiang,Gao Ruize,Nie Junli,Xie Jiaying,Han Jinxue,Chen Linbo,Ma Gui,Zhu Yushan,Chen Quan Nature communications The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer. 10.1038/s41467-019-08618-y
    An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression. Palazon Asis,Tyrakis Petros A,Macias David,Veliça Pedro,Rundqvist Helene,Fitzpatrick Susan,Vojnovic Nikola,Phan Anthony T,Loman Niklas,Hedenfalk Ingrid,Hatschek Thomas,Lövrot John,Foukakis Theodoros,Goldrath Ananda W,Bergh Jonas,Johnson Randall S Cancer cell Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8 T cells. Furthermore, loss of HIF-1α in CD8 T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8 T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8 T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity. 10.1016/j.ccell.2017.10.003
    Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cooke Vesselina G,LeBleu Valerie S,Keskin Doruk,Khan Zainab,O'Connell Joyce T,Teng Yingqi,Duncan Michael B,Xie Liang,Maeda Genta,Vong Sylvia,Sugimoto Hikaru,Rocha Rafael M,Damascena Aline,Brentani Ricardo R,Kalluri Raghu Cancer cell The functional role of pericytes in cancer progression remains unknown. Clinical studies suggest that low numbers of vessel-associated pericytes correlated with a drop in overall survival of patients with invasive breast cancer. Using genetic mouse models or pharmacological inhibitors, pericyte depletion suppressed tumor growth but enhanced metastasis. Pericyte depletion was further associated with increased hypoxia, epithelial-to-mesenchymal transition (EMT), and Met receptor activation. Silencing of Twist or use of a Met inhibitor suppressed hypoxia and EMT/Met-driven metastasis. In addition, poor pericyte coverage coupled with high Met expression in cancer cells speculates the worst prognosis for patients with invasive breast cancer. Collectively, our study suggests that pericytes within the primary tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis. 10.1016/j.ccr.2011.11.024
    Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit. Costales Matthew G,Haga Christopher L,Velagapudi Sai Pradeep,Childs-Disney Jessica L,Phinney Donald G,Disney Matthew D Journal of the American Chemical Society A hypoxic state is critical to the metastatic and invasive characteristics of cancer. Numerous pathways play critical roles in cancer maintenance, many of which include noncoding RNAs such as microRNA (miR)-210 that regulates hypoxia inducible factors (HIFs). Herein, we describe the identification of a small molecule named Targapremir-210 that binds to the Dicer site of the miR-210 hairpin precursor. This interaction inhibits production of the mature miRNA, derepresses glycerol-3-phosphate dehydrogenase 1-like enzyme (GPD1L), a hypoxia-associated protein negatively regulated by miR-210, decreases HIF-1α, and triggers apoptosis of triple negative breast cancer cells only under hypoxic conditions. Further, Targapremir-210 inhibits tumorigenesis in a mouse xenograft model of hypoxic triple negative breast cancer. Many factors govern molecular recognition of biological targets by small molecules. For protein, chemoproteomics and activity-based protein profiling are invaluable tools to study small molecule target engagement and selectivity in cells. Such approaches are lacking for RNA, leaving a void in the understanding of its druggability. We applied Chemical Cross-Linking and Isolation by Pull Down (Chem-CLIP) to study the cellular selectivity and the on- and off-targets of Targapremir-210. Targapremir-210 selectively recognizes the miR-210 precursor and can differentially recognize RNAs in cells that have the same target motif but have different expression levels, revealing this important feature for selectively drugging RNAs for the first time. These studies show that small molecules can be rapidly designed to selectively target RNAs and affect cellular responses to environmental conditions, resulting in favorable benefits against cancer. Further, they help define rules for identifying druggable targets in the transcriptome. 10.1021/jacs.6b11273
    Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Ma Biao,Chen Yan,Chen Ling,Cheng Hongcheng,Mu Chenglong,Li Jie,Gao Ruize,Zhou Changqian,Cao Lei,Liu Jinhua,Zhu Yushan,Chen Quan,Wu Shian Nature cell biology The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis. Understanding how the activity of this pathway is regulated by the cellular microenvironment remains a major challenge. Here we elucidate a molecular mechanism by which hypoxia deactivates Hippo signalling. We demonstrate that the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in a xenograft mouse model. We further show that YAP complexes with HIF1α and is essential for HIF1α stability and function in tumours in vivo. LATS2 is downregulated in human breast tumours and negatively correlates with SIAH2 expression levels, indicating that the SIAH2-LATS2 pathway may have a role in human cancer. Our data uncover oxygen availability as a microenvironment signal for the Hippo pathway and have implications for understanding the regulation of Hippo signalling in tumorigenesis. 10.1038/ncb3073
    PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Banh Robert S,Iorio Caterina,Marcotte Richard,Xu Yang,Cojocari Dan,Rahman Anas Abdel,Pawling Judy,Zhang Wei,Sinha Ankit,Rose Christopher M,Isasa Marta,Zhang Shuang,Wu Ronald,Virtanen Carl,Hitomi Toshiaki,Habu Toshiyuki,Sidhu Sachdev S,Koizumi Akio,Wilkins Sarah E,Kislinger Thomas,Gygi Steven P,Schofield Christopher J,Dennis James W,Wouters Bradly G,Neel Benjamin G Nature cell biology Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2(+) xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2(+) BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2(+) BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment. 10.1038/ncb3376
    Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance. Xiong Gaofeng,Stewart Rachel L,Chen Jie,Gao Tianyan,Scott Timothy L,Samayoa Luis M,O'Connor Kathleen,Lane Andrew N,Xu Ren Nature communications Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. We also show that increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy. These results suggest that P4HA1 promotes chemoresistance by modulating HIF-1-dependent cancer cell stemness. Targeting collagen P4H is a promising strategy to inhibit tumor progression and sensitize TNBC to chemotherapeutic agents. 10.1038/s41467-018-06893-9
    A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis. Rezaeian Abdol-Hossein,Li Chien-Feng,Wu Ching-Yuan,Zhang Xian,Delacerda Jorge,You M James,Han Fei,Cai Zhen,Jeong Yun Seong,Jin Guoxiang,Phan Liem,Chou Ping-Chieh,Lee Mong-Hong,Hung Mien-Chie,Sarbassov Dos,Lin Hui-Kuan Nature cell biology The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumorigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy. 10.1038/ncb3445
    miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Wu Min-Zu,Cheng Wei-Chung,Chen Su-Feng,Nieh Shin,O'Connor Carolyn,Liu Chia-Lin,Tsai Wen-Wei,Wu Cheng-Jang,Martin Lorena,Lin Yaoh-Shiang,Wu Kou-Juey,Lu Li-Fan,Izpisua Belmonte Juan Carlos Nature cell biology The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies. 10.1038/ncb3615
    Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Dong Chenfang,Yuan Tingting,Wu Yadi,Wang Yifan,Fan Teresa W M,Miriyala Sumitra,Lin Yiwei,Yao Jun,Shi Jian,Kang Tiebang,Lorkiewicz Pawel,St Clair Daret,Hung Mien-Chie,Evers B Mark,Zhou Binhua P Cancer cell The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecule biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and reactive oxygen species production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with T-cell factor. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC. 10.1016/j.ccr.2013.01.022
    Diverse roles of cell-specific hypoxia-inducible factor 1 in cancer-associated hypercoagulation. Evans Colin E,Bendahl Pär-Ola,Belting Mattias,Branco Cristina,Johnson Randall S Blood Despite the increased risk of thrombosis in cancer patients compared with healthy individuals, mechanisms that regulate cancer-induced hypercoagulation are incompletely understood. The aim of this study was to investigate whether cell-specific hypoxia-inducible factor (HIF) 1α regulates cancer-associated hypercoagulation, using in vitro clotting assays and in vivo cancer models. In mouse lung and mammary tumor cells, hypoxia led to increases in cell adhesion, clotting, and fibrin deposition; these increases were eliminated in HIF1α null cells. Increased levels of HIF1α were also associated with increased tissue factor expression in human breast tumor samples. Conversely, deletion of endothelial (but not myeloid) cell-specific HIF1α doubled pulmonary fibrin deposition, and trebled thrombus formation compared with wildtype littermates in tumor-bearing mice. Our data suggest that tumor and endothelial cell-specific HIF1α may have opposing roles in cancer-associated coagulation and thrombosis. Off-target effects of manipulating the HIF1 axis in cancer patients should be carefully considered when managing thrombotic complications. 10.1182/blood-2015-09-671982
    Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal. Zhou Bing,Damrauer Jeffrey S,Bailey Sean T,Hadzic Tanja,Jeong Youngtae,Clark Kelly,Fan Cheng,Murphy Laura,Lee Cleo Y,Troester Melissa A,Miller C Ryan,Jin Jian,Darr David,Perou Charles M,Levine Ross L,Diehn Maximilian,Kim William Y The Journal of clinical investigation Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy. 10.1172/JCI69804
    Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression. Liu Juan,Zhang Cen,Zhao Yuhan,Yue Xuetian,Wu Hao,Huang Shan,Chen James,Tomsky Kyle,Xie Haiyang,Khella Christen A,Gatza Michael L,Xia Dajing,Gao Jimin,White Eileen,Haffty Bruce G,Hu Wenwei,Feng Zhaohui Nature communications Mutations in E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Accumulating evidence suggests that Parkin is a tumor suppressor, but the underlying mechanism is poorly understood. Here we show that Parkin is an E3 ubiquitin ligase for hypoxia-inducible factor 1α (HIF-1α). Parkin interacts with HIF-1α and promotes HIF-1α degradation through ubiquitination, which in turn inhibits metastasis of breast cancer cells. Parkin downregulation in breast cancer cells promotes metastasis, which can be inhibited by targeting HIF-1α with RNA interference or the small-molecule inhibitor YC-1. We further identify lysine 477 (K477) of HIF-1α as a major ubiquitination site for Parkin. K477R HIF-1α mutation and specific cancer-associated Parkin mutations largely abolish the functions of Parkin to ubiquitinate HIF-1α and inhibit cancer metastasis. Importantly, Parkin expression is inversely correlated with HIF-1α expression and metastasis in breast cancer. Our results reveal an important mechanism for Parkin in tumor suppression and HIF-1α regulation. 10.1038/s41467-017-01947-w
    The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Lin Aifu,Li Chunlai,Xing Zhen,Hu Qingsong,Liang Ke,Han Leng,Wang Cheng,Hawke David H,Wang Shouyu,Zhang Yanyan,Wei Yongkun,Ma Guolin,Park Peter K,Zhou Jianwei,Zhou Yan,Hu Zhibin,Zhou Yubin,Marks Jeffery R,Liang Han,Hung Mien-Chie,Lin Chunru,Yang Liuqing Nature cell biology Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer. 10.1038/ncb3295
    Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Briggs Kimberly J,Koivunen Peppi,Cao Shugeng,Backus Keriann M,Olenchock Benjamin A,Patel Hetalben,Zhang Qing,Signoretti Sabina,Gerfen Gary J,Richardson Andrea L,Witkiewicz Agnieszka K,Cravatt Benjamin F,Clardy Jon,Kaelin William G Cell The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIFα prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1α accumulation. Therefore, EglN1 senses both oxygen and cysteine. 10.1016/j.cell.2016.05.042
    XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Chen Xi,Iliopoulos Dimitrios,Zhang Qing,Tang Qianzi,Greenblatt Matthew B,Hatziapostolou Maria,Lim Elgene,Tam Wai Leong,Ni Min,Chen Yiwen,Mai Junhua,Shen Haifa,Hu Dorothy Z,Adoro Stanley,Hu Bella,Song Minkyung,Tan Chen,Landis Melissa D,Ferrari Mauro,Shin Sandra J,Brown Myles,Chang Jenny C,Liu X Shirley,Glimcher Laurie H Nature Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer. 10.1038/nature13119
    FOXK2 Elicits Massive Transcription Repression and Suppresses the Hypoxic Response and Breast Cancer Carcinogenesis. Shan Lin,Zhou Xing,Liu Xinhua,Wang Yue,Su Dongxue,Hou Yongqiang,Yu Na,Yang Chao,Liu Beibei,Gao Jie,Duan Yang,Yang Jianguo,Li Wanjin,Liang Jing,Sun Luyang,Chen Kexin,Xuan Chenghao,Shi Lei,Wang Yan,Shang Yongfeng Cancer cell Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1β and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1β/EZH2. Significantly, the expression of FOXK2 is progressively lost during breast cancer progression, and low FOXK2 expression is strongly correlated with higher histologic grades, positive lymph nodes, and ERα/PR/HER2 status, all indicators of poor prognosis. 10.1016/j.ccell.2016.09.010
    Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. Chaturvedi Pallavi,Gilkes Daniele M,Wong Carmen Chak Lui, ,Luo Weibo,Zhang Huafeng,Wei Hong,Takano Naoharu,Schito Luana,Levchenko Andre,Semenza Gregg L The Journal of clinical investigation Metastasis involves critical interactions between cancer and stromal cells. Intratumoral hypoxia promotes metastasis through activation of hypoxia-inducible factors (HIFs). We demonstrate that HIFs mediate paracrine signaling between breast cancer cells (BCCs) and mesenchymal stem cells (MSCs) to promote metastasis. In a mouse orthotopic implantation model, MSCs were recruited to primary breast tumors and promoted BCC metastasis to LNs and lungs in a HIF-dependent manner. Coculture of MSCs with BCCs augmented HIF activity in BCCs. Additionally, coculture induced expression of the chemokine CXCL10 in MSCs and the cognate receptor CXCR3 in BCCs, which was augmented by hypoxia. CXCR3 expression was blocked in cocultures treated with neutralizing antibody against CXCL10. Conversely, CXCL10 expression was blocked in MSCs cocultured with BCCs that did not express CXCR3 or HIFs. MSC coculture did not enhance the metastasis of HIF-deficient BCCs. BCCs and MSCs expressed placental growth factor (PGF) and its cognate receptor VEGFR1, respectively, in a HIF-dependent manner, and CXCL10 expression by MSCs was dependent on PGF expression by BCCs. PGF promoted metastasis of BCCs and also facilitated homing of MSCs to tumors. Thus, HIFs mediate complex and bidirectional paracrine signaling between BCCs and MSCs that stimulates breast cancer metastasis. 10.1172/JCI64993
    PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer. Dupuy Fanny,Tabariès Sébastien,Andrzejewski Sylvia,Dong Zhifeng,Blagih Julianna,Annis Matthew G,Omeroglu Atilla,Gao Dongxia,Leung Samuel,Amir Eitan,Clemons Mark,Aguilar-Mahecha Adriana,Basik Mark,Vincent Emma E,St-Pierre Julie,Jones Russell G,Siegel Peter M Cell metabolism Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone- or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer. 10.1016/j.cmet.2015.08.007
    Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence. Rios Garcia Marcos,Steinbauer Brigitte,Srivastava Kshitij,Singhal Mahak,Mattijssen Frits,Maida Adriano,Christian Sven,Hess-Stumpp Holger,Augustin Hellmut G,Müller-Decker Karin,Nawroth Peter P,Herzig Stephan,Berriel Diaz Mauricio Cell metabolism Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy. 10.1016/j.cmet.2017.09.018
    Macrophages as regulators of tumour immunity and immunotherapy. DeNardo David G,Ruffell Brian Nature reviews. Immunology Macrophages are critical mediators of tissue homeostasis, with tumours distorting this proclivity to stimulate proliferation, angiogenesis and metastasis. This had led to an interest in targeting macrophages in cancer, and preclinical studies have demonstrated efficacy across therapeutic modalities and tumour types. Much of the observed efficacy can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis. As a result, tumour macrophages display an ability to suppress T cell recruitment and function as well as to regulate other aspects of tumour immunity. With the increasing impact of cancer immunotherapy, macrophage targeting is now being evaluated in this context. Here, we discuss the results of clinical trials and the future of combinatorial immunotherapy. 10.1038/s41577-019-0127-6
    Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. Semenza Gregg L The EMBO journal Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer. 10.15252/embj.201695204
    HIF2-Induced Long Noncoding RNA RAB11B-AS1 Promotes Hypoxia-Mediated Angiogenesis and Breast Cancer Metastasis. Niu Yanling,Bao Lei,Chen Yan,Wang Chenliang,Luo Maowu,Zhang Bo,Zhou Mi,Wang Jennifer E,Fang Yisheng V,Kumar Ashwani,Xing Chao,Wang Yingfei,Luo Weibo Cancer research Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells . Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis. SIGNIFICANCE: This study reveals the molecular mechanism by which the lncRNA RAB11B-AS1 regulates hypoxia-induced angiogenesis and breast cancer metastasis, and provides new insights into the functional interaction between a lncRNA and tumor microenvironment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/5/964/F1.large.jpg. 10.1158/0008-5472.CAN-19-1532
    HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia. Li Xinyan,Wang Mengshen,Li Su,Chen Yuqiong,Wang Mozhi,Wu Zhonghua,Sun Xiangyu,Yao Litong,Dong Haoran,Song Yongxi,Xu Yingying Theranostics Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria. A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O environment. MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells. This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment. 10.7150/thno.57804
    Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer. Chang Po-Hao,Chen Min-Che,Tsai Ya-Ping,Tan Grace Y T,Hsu Pang-Hung,Jeng Yung-Ming,Tsai Yi-Fang,Yang Muh-Hwa,Hwang-Verslues Wendy W Proceedings of the National Academy of Sciences of the United States of America Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis. 10.1073/pnas.2014408118
    Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis. Wang Ru,Godet Ines,Yang Yongkang,Salman Shaima,Lu Haiquan,Lyu Yajing,Zuo Qiaozhu,Wang Yufeng,Zhu Yayun,Chen Chelsey,He Jianjun,Gilkes Daniele M,Semenza Gregg L Proceedings of the National Academy of Sciences of the United States of America Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice. 10.1073/pnas.2020490118
    Hypoxia-inducible factors promote breast cancer stem cell specification and maintenance in response to hypoxia or cytotoxic chemotherapy. Xiang Lisha,Semenza Gregg L Advances in cancer research Clinical studies have revealed that breast cancers contain regions of intratumoral hypoxia (reduced oxygen availability), which activates hypoxia-inducible factors (HIFs). The relationship between intratumoral hypoxia, distant metastasis and cancer mortality has been well established. A major mechanism by which intratumoral hypoxia contributes to disease progression is through induction of the breast cancer stem cell (BCSC) phenotype. BCSCs are a small subpopulation of cells with the capability for self-renewal. BCSCs have been implicated in resistance to chemotherapy, disease recurrence, and metastasis. In this review, we will discuss our current understanding of the molecular mechanisms underlying HIF-dependent induction of the BCSC phenotype in response to hypoxia or chemotherapy. 10.1016/bs.acr.2018.11.001
    HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. de Heer Ellen C,Jalving Mathilde,Harris Adrian L The Journal of clinical investigation Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment. 10.1172/JCI137552