YAP promotes autophagy and progression of gliomas via upregulating HMGB1. Zhao Min,Zhang Yu,Jiang Yang,Wang Kai,Wang Xiang,Zhou Ding,Wang Yan,Yu Rutong,Zhou Xiuping Journal of experimental & clinical cancer research : CR BACKGROUND:Due to the hypoxia and nutrient deficiency microenvironment, glioblastoma (GBM) exhibits high autophagy activity and autophagy plays an important role in the progression of GBM. However, the molecular mechanism of autophagy in GBM progression remains unclear. The aim of this study is to delve out the role and mechanism of yes-associated protein (YAP) in GBM autophagy and progression. METHODS:The level of autophagy or autophagy flux were assessed by using western blotting, GFP-LC3 puncta (Live) imaging, transmission electron microscopy and GFP-RFP-LC3 assay. The GBM progression was detected by using CCK8, EdU, nude mouse xenograft and Ki67 staining. Isobaric tags for relative and absolute quantification (iTraq) quantitative proteomics was used to find out the mediator of YAP in autophagy. Expression levels of YAP and HMGB1 in tissue samples from GBM patients were examined by Western blotting, tissue microarray and immunohistochemistry. RESULTS:YAP over-expression enhanced glioma cell autophagy under basal and induced conditions. In addition, blocking autophagy by chloroquine abolished the promoting effect of YAP on glioma growth. Mechanistically, YAP over-expression promoted the transcription and translocation of high mobility group box 1(HMGB1), a well-known regulator of autophagy, from nucleus to cytoplasm. Down-regulation of HMGB1 abolished the promoting effect of YAP on autophagy and glioma growth. Furthermore, the expression of YAP and HMGB1 were positively associated with each other and suggested poor prognosis for clinical GBM. CONCLUSION:YAP promoted glioma progression by enhancing HMGB1-mediated autophagy, indicating that YAP-HMGB1 axis was a feasible therapeutic target for GBM. Our study revealed a clinical opportunity involving the combination of chemo-radiotherapy with pharmacological autophagy inhibition for treating GBM patients with YAP high expression. 10.1186/s13046-021-01897-8
    YAP promotes multi-drug resistance and inhibits autophagy-related cell death in hepatocellular carcinoma via the RAC1-ROS-mTOR pathway. Zhou Yuan,Wang Yubo,Zhou Wuhua,Chen Tianchi,Wu Qinchuan,Chutturghoon Vikram Kumar,Lin Bingyi,Geng Lei,Yang Zhe,Zhou Lin,Zheng Shusen Cancer cell international Background:Multi-drug resistance is the major cause of chemotherapy failure in hepatocellular carcinoma (HCC). YAP, a critical effector of the Hippo pathway, has been shown to contribute to the progression, metastasis and invasion of cancers. However, the potential role of YAP in mediating drug resistance remains obscure. Methods:RT-qPCR and western blot were used to assess YAP expression in HCC cell lines. CCK-8 assays, flow cytometry, a xenograft tumour model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on multi-drug resistance, intracellular ROS production and the autophagy of HCC cells in vitro and in vivo. Autophagy inhibitor and rescue experiments were carried out to elucidate the mechanism by which YAP promotes chemoresistance in HCC cells. Results:We found that BEL/FU, a typical HCC cell line with chemoresistance, exhibited overexpression of YAP. Moreover, the inhibition of YAP by shRNA or verteporfin conferred the sensitivity of BEL/FU cells to chemotherapeutic agents through autophagy-related cell death in vitro and in vivo. Mechanistically, YAP silencing significantly enhanced autophagic flux by increasing RAC1-driven ROS, which contributed to the inactivation of mTOR in HCC cells. In addition, the antagonist of autophagy reversed the enhanced effect of YAP silencing on cell death under treatment with chemotherapeutic agents. Conclusion:Our findings suggested that YAP upregulation endowed HCC cells with multi-drug resistance via the RAC1-ROS-mTOR pathway, resulting in the repression of autophagy-related cell death. The blockade of YAP may serve as a promising novel therapeutic strategy for overcoming chemoresistance in HCC. 10.1186/s12935-019-0898-7
    Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. Liang Ning,Zhang Chi,Dill Patricia,Panasyuk Ganna,Pion Delphine,Koka Vonda,Gallazzini Morgan,Olson Eric N,Lam Hilaire,Henske Elizabeth P,Dong Zheng,Apte Udayan,Pallet Nicolas,Johnson Randy L,Terzi Fabiola,Kwiatkowski David J,Scoazec Jean-Yves,Martignoni Guido,Pende Mario The Journal of experimental medicine Genetic studies have shown that the tuberous sclerosis complex (TSC) 1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity. 10.1084/jem.20140341
    α-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation. Pavel Mariana,Park So Jung,Frake Rebecca A,Son Sung Min,Manni Marco M,Bento Carla F,Renna Maurizio,Ricketts Thomas,Menzies Fiona M,Tanasa Radu,Rubinsztein David C Nature communications The factors regulating cellular identity are critical for understanding the transition from health to disease and responses to therapies. Recent literature suggests that autophagy compromise may cause opposite effects in different contexts by either activating or inhibiting YAP/TAZ co-transcriptional regulators of the Hippo pathway via unrelated mechanisms. Here, we confirm that autophagy perturbation in different cell types can cause opposite responses in growth-promoting oncogenic YAP/TAZ transcriptional signalling. These apparently contradictory responses can be resolved by a feedback loop where autophagy negatively regulates the levels of α-catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of α-catenins enable autophagy induction to positively regulate YAP/TAZ, while low α-catenins cause YAP/TAZ activation upon autophagy inhibition. These data reveal how feedback loops enable post-transcriptional determination of cell identity and how levels of a single intermediary protein can dictate the direction of response to external or internal perturbations. 10.1038/s41467-021-21882-1
    Role of Apigenin in Cancer Prevention via the Induction of Apoptosis and Autophagy. Sung Bokyung,Chung Hae Young,Kim Nam Deuk Journal of cancer prevention Apigenin (4',5,7-trihydroxyflavone) is a flavonoid commonly found in many fruits and vegetables such as parsley, chamomile, celery, and kumquats. In the last few decades, recognition of apigenin as a cancer chemopreventive agent has increased. Significant progress has been made in studying the chemopreventive aspects of apigenin both in vitro and in vivo. Several studies have demonstrated that the anticarcinogenic properties of apigenin occur through regulation of cellular response to oxidative stress and DNA damage, suppression of inflammation and angiogenesis, retardation of cell proliferation, and induction of autophagy and apoptosis. One of the most well-recognized mechanisms of apigenin is the capability to promote cell cycle arrest and induction of apoptosis through the p53-related pathway. A further role of apigenin in chemoprevention is the induction of autophagy in several human cancer cell lines. In this review, we discuss the details of apigenin, apoptosis, autophagy, and the role of apigenin in cancer chemoprevention via the induction of apoptosis and autophagy. 10.15430/JCP.2016.21.4.216
    Autophagy promotes triple negative breast cancer metastasis via YAP nuclear localization. Chen Wei,Bai Yuxin,Patel Chrishma,Geng Fei Biochemical and biophysical research communications The triple-negative breast cancer (TNBC) subtype is the most aggressive form of invasive breast cancer. Although autophagy is critical to the progression of TNBC, the mechanism of autophagy in regulating the metastatic potential of TNBC still remains unclear. Recently, the effector of the Hippo signaling pathway yes-associated protein (YAP) was shown to promote autophagy. To investigate autophagy regulation in YAP signaling in the context of cancer metastasis, we performed profiling analysis of YAP signaling, YAP subcellular localization, autophagosome formation and cell invasiveness in TNBC cell lines (MDA-MB-231 and Hs 578T) versus estrogen receptor (ER) positive breast cancer cell line MCF7. Our results showed that YAP transcriptional and protein expression was significantly upregulated in TNBC. When we triggered autophagy response in TNBC, YAP translocated into the nucleus and the expression of YAP target gene ankyrin repeat domain 1 (ANKRD1) increased remarkably. The correlation between autophagy response and YAP expression in TNBC was confirmed at the single-cell level. Furthermore, the inhibition of YAP nuclear entry greatly impeded the migration and invasion of TNBC cells while it did not affect the mobility of ER positive breast cancer cells. Therefore, this research established the autophagy-YAP-metastasis axis in TNBC and sheds light on the application of targeting YAP for TNBC therapeutics. 10.1016/j.bbrc.2019.09.133
    Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment. Liu Fang-Lan,Mo En-Pan,Yang Liu,Du Jun,Wang Hong-Sheng,Zhang Huan,Kurihara Hiroshi,Xu Jun,Cai Shao-Hui Oncotarget Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer. 10.18632/oncotarget.6702