New insights into the interplay between long non-coding RNAs and RNA-binding proteins in cancer.
Cancer communications (London, England)
With the development of proteomics and epigenetics, a large number of RNA-binding proteins (RBPs) have been discovered in recent years, and the interaction between long non-coding RNAs (lncRNAs) and RBPs has also received increasing attention. It is extremely important to conduct in-depth research on the lncRNA-RBP interaction network, especially in the context of its role in the occurrence and development of cancer. Increasing evidence has demonstrated that lncRNA-RBP interactions play a vital role in cancer progression; therefore, targeting these interactions could provide new insights for cancer drug discovery. In this review, we discussed how lncRNAs can interact with RBPs to regulate their localization, modification, stability, and activity and discussed the effects of RBPs on the stability, transport, transcription, and localization of lncRNAs. Moreover, we explored the regulation and influence of these interactions on lncRNAs, RBPs, and downstream pathways that are related to cancer development, such as N6-methyladenosine (m6A) modification of lncRNAs. In addition, we discussed how the lncRNA-RBP interaction network regulates cancer cell phenotypes, such as proliferation, apoptosis, metastasis, drug resistance, immunity, tumor environment, and metabolism. Furthermore, we summarized the therapeutic strategies that target the lncRNA-RBP interaction network. Although these treatments are still in the experimental stage and various theories and processes are still being studied, we believe that these strategies may provide new ideas for cancer treatment.
10.1002/cac2.12254
Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia.
Wu C J,Yang X F,McLaughlin S,Neuberg D,Canning C,Stein B,Alyea E P,Soiffer R J,Dranoff G,Ritz J
The Journal of clinical investigation
The effectiveness of donor-lymphocyte infusion (DLI) for treatment of relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation is a clear demonstration of the graft-versus-leukemia (GVL) effect. T cells are critical mediators of GVL, but the antigenic targets of this response are unknown. To determine whether patients who respond to DLI also develop B-cell immunity to CML-associated antigens, we analyzed sera from three patients with relapsed CML who achieved a complete molecular remission after infusion of donor T cells. Sera from these individuals recognized 13 distinct gene products represented in a CML-derived cDNA library. Two proteins, Jkappa-recombination signal-binding protein (RBP-Jkappa) and related adhesion focal tyrosine kinase (RAFTK), were recognized by sera from three of 19 DLI responders. None of these antigens were recognized by sera from healthy donors or patients with chronic graft-versus-host disease. Four gene products were recognized by sera from CML patients treated with hydroxyurea and nine were detected by sera from CML patients who responded to IFN-alpha. Antibody titers specific for RAFTK, but not for RBP-Jkappa, were found to be temporally associated with the response to DLI. These results demonstrate that patients who respond to DLI generate potent antibody responses to CML-associated antigens, suggesting the development of coordinated T- and B-cell immunity. The characterization of B cell-defined antigens may help identify clinically relevant targets of the GVL response in vivo.
10.1172/JCI10196
Identification of an individualized RNA binding protein-based prognostic signature for diffuse large B-cell lymphoma.
Xie Yongzhi,Luo Ximei,He Haiqing,Pan Tao,He Yizi
Cancer medicine
RNA binding proteins (RBPs) are increasingly appreciated as being essential for normal hematopoiesis and have a critical role in the progression of hematological malignancies. However, their functional consequences and clinical significance in diffuse large B-cell lymphoma (DLBCL) remain unknown. Here, we conducted a systematic analysis to identify RBP-related genes affecting DLBCL prognosis based on the Gene Expression Omnibus database. By univariate and multivariate Cox proportional hazards regression (CPHR) methods, six RBPs-related genes (CMSS1, MAEL, THOC5, PSIP1, SNIP1, and ZCCHC7) were identified closely related to the overall survival (OS) of DLBCL patients. The RBPs signature could efficiently distinguished low-risk from high-risk patients and could serve as an independent and reliable factor for predicting OS. Moreover, Gene Set Enrichment Analysis revealed 17 significantly enriched pathways between high- versus low-risk group, including the regulation of autophagy, chronic myeloid leukemia, NOTCH signaling pathway, and B cell receptor signaling pathway. Then we developed an RBP-based nomogram combining other clinical risk factors. The receiver operating characteristic curve analysis demonstrated high prognostic predictive efficiency of this model with the area under the curve values were 0.820 and 0.780, respectively, in the primary set and entire set. In summary, our RBP-based model could be a novel prognostic predictor and had the potential for developing treatment targets for DLBCL.
10.1002/cam4.3859
Expression of leukemia inhibitory factor in Müller glia cells is regulated by a redox-dependent mRNA stability mechanism.
Agca Cavit,Boldt Karsten,Gubler Andrea,Meneau Isabelle,Corpet Armelle,Samardzija Marijana,Stucki Manuel,Ueffing Marius,Grimm Christian
BMC biology
BACKGROUND:Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Müller glia cells in response to photoreceptor damage. RESULTS:We present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Müller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3'UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox-dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Müller cells. CONCLUSIONS:Our results suggest that H2O2-induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo.
10.1186/s12915-015-0137-1
A noncanonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.
Blood
RNA-binding proteins (RBPs) form a large and diverse class of factors, many members of which are overexpressed in hematologic malignancies. RBPs participate in various processes of messenger RNA (mRNA) metabolism and prevent harmful DNA:RNA hybrids or R-loops. Here, we report that PIWIL4, a germ stem cell-associated RBP belonging to the RNase H-like superfamily, is overexpressed in patients with acute myeloid leukemia (AML) and is essential for leukemic stem cell function and AML growth, but dispensable for healthy human hematopoietic stem cells. In AML cells, PIWIL4 binds to a small number of known piwi-interacting RNA. Instead, it largely interacts with mRNA annotated to protein-coding genic regions and enhancers that are enriched for genes associated with cancer and human myeloid progenitor gene signatures. PIWIL4 depletion in AML cells downregulates the human myeloid progenitor signature and leukemia stem cell (LSC)-associated genes and upregulates DNA damage signaling. We demonstrate that PIWIL4 is an R-loop resolving enzyme that prevents R-loop accumulation on a subset of AML and LSC-associated genes and maintains their expression. It also prevents DNA damage, replication stress, and activation of the ATR pathway in AML cells. PIWIL4 depletion potentiates sensitivity to pharmacological inhibition of the ATR pathway and creates a pharmacologically actionable dependency in AML cells.
10.1182/blood.2022018651
RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.
Haematologica
RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.
10.3324/haematol.2022.282066
Reduced serum retinol-binding protein levels in patients with de novo acute myeloid leukaemia.
Su Long,Gao Sujun,Tan YeHui,Yang Yan,Liu XiaoLiang,Yu Ping,Lin Hai,Li Wei
Hematology (Amsterdam, Netherlands)
Retinol-binding protein (RBP) has been used as a nutritional index for children with acute myeloid leukaemia (AML) in previous studies. However, no studies have yet examined RBP levels in AML patients from all age groups. In this study, AML patients presented with lower RBP concentrations than healthy control subjects and patients with benign haematopathies. A negative association was observed between serum RBP level and peripheral white blood cell count in M4 and M5 AML patients. Moreover, patients carrying the FLT3-ITD mutation and young patients had lower RBP levels than those lacking this mutation and elderly patients. In conclusion, these observations suggest that aberrant retinol levels may be associated with AML.
10.1179/1607845413Y.0000000091
Systematic Construction and Validation of an RNA-Binding Protein-Associated Prognostic Model for Acute Myeloid Leukemia.
Luo Hongwei,Zhang Yingchun,Hu Nan,He Yancheng,He Chengcheng
Frontiers in genetics
The abnormal expression of RNA-binding proteins (RBPs) in various malignant tumors is closely related to the occurrence and development of tumors. However, the role of RBPs in acute myeloid leukemia (AML) is unclear. We downloaded harmonized RNA-seq count data and clinical data for AML from UCSC Xena, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohorts. R package was used for differential expression analysis of 337 whole-blood data and 173 AML data. The prognostic value of these RBPs was systematically investigated by using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO)-Cox regression analysis, and multivariate Cox regression analysis. C-index and calibration diagram were used to judge the accuracy of the model, and decision curve analysis (DCA) was used to judge the net benefit. The biological pathways involved were revealed by gene set enrichment analysis (GSEA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein-protein interaction (PPI) network performed lateral verification on the selected gene set and LASSO results. A prognostic model of 12-RBP signature was established. In addition, the net benefit and prediction accuracy of the prognostic model and the mixed model based on it were significantly higher than that of cytogenetics. It is verified in the TARGET cohort and shows good prediction effect. Both the selection of our gene set and the LASSO results have high credibility. Most of these pathways are involved in the development of the disease, and they also accumulate in leukemia and RNA-related pathways. The prognosis model of the 12-RBP signature found in this study is an optimized biomarker that can effectively stratify the risk of AML patients. Nomogram based on this prognostic model is a reliable method to predict the median survival time of patients. This study expands our current understanding of the role of RBPs in the occurrence of AML and may lay the foundation for future treatment of the disease.
10.3389/fgene.2021.715840
Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML.
Blood advances
A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558.
10.1182/bloodadvances.2022008806
A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation.
Davis Amanda G,Einstein Jaclyn M,Zheng Dinghai,Jayne Nathan D,Fu Xiang-Dong,Tian Bin,Yeo Gene W,Zhang Dong-Er
Blood advances
The proper balance of hematopoietic stem cell (HSC) self-renewal and differentiation is critical for normal hematopoiesis and is disrupted in hematologic malignancy. Among regulators of HSC fate, transcription factors have a well-defined central role, and mutations promote malignant transformation. More recently, studies have illuminated the importance of posttranscriptional regulation by RNA-binding proteins (RBPs) in hematopoiesis and leukemia development. However, the RBPs involved and the breadth of regulation are only beginning to be elucidated. Furthermore, the intersection between posttranscriptional regulation and hematopoietic transcription factor function is poorly understood. Here, we studied the posttranscriptional regulation of RUNX1, a key hematopoietic transcription factor. Alternative polyadenylation (APA) of RUNX1 produces functionally antagonistic protein isoforms (RUNX1a vs RUNX1b/c) that mediate HSC self-renewal vs differentiation, an RNA-processing event that is dysregulated in malignancy. Consequently, RBPs that regulate this event directly contribute to healthy and aberrant hematopoiesis. We modeled RUNX1 APA using a split GFP minigene reporter and confirmed the sensitivity of our model to detect changes in RNA processing. We used this reporter in a clustered regularly interspaced short palindromic repeats (CRISPR) screen consisting of single guide RNAs exclusively targeting RBPs and uncovered HNRNPA1 and KHDRBS1 as antagonistic regulators of RUNX1a isoform generation. Overall, our study provides mechanistic insight into the posttranscriptional regulation of a key hematopoietic transcription factor and identifies RBPs that may have widespread and important functions in hematopoiesis.
10.1182/bloodadvances.2020002090
AU-rich RNA binding proteins in hematopoiesis and leukemogenesis.
Baou Maria,Norton John D,Murphy John J
Blood
Posttranscriptional mechanisms are now widely acknowledged to play a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation, and tumorigenesis. Although much attention has focused on microRNAs as regulators of mRNA stability/translation, recent data have highlighted the role of several diverse classes of AU-rich RNA-binding protein in the regulation of mRNA decay/stabilization. AU-rich elements are found in the 3'-untranslated region of many mRNAs that encode regulators of cell growth and survival, such as cytokines and onco/tumor-suppressor proteins. These are targeted by a burgeoning number of different RNA-binding proteins. Three distinct types of AU-rich RNA binding protein (ARE poly-U-binding degradation factor-1/AUF1, Hu antigen/HuR/HuA/ELAVL1, and the tristetraprolin/ZFP36 family of proteins) are essential for normal hematopoiesis. Together with 2 further AU-rich RNA-binding proteins, nucleolin and KHSRP/KSRP, the functions of these proteins are intimately associated with pathways that are dysregulated in various hematopoietic malignancies. Significantly, all of these AU-rich RNA-binding proteins function via an interconnected network that is integrated with microRNA functions. Studies of these diverse types of RNA binding protein are providing novel insight into gene-regulatory mechanisms in hematopoiesis in addition to offering new opportunities for developing mechanism-based targeted therapeutics in leukemia and lymphoma.
10.1182/blood-2011-07-347237
IGF2BP family of RNA-binding proteins regulate innate and adaptive immune responses in cancer cells and tumor microenvironment.
Frontiers in immunology
Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3) are a family of RNA-binding proteins that play an essential role in the development and disease by regulating mRNA stability and translation of critical regulators of cell division and metabolism. Genetic and chemical inhibition of these proteins slows down cancer cell proliferation, decreases invasiveness, and prolongs life span in a variety of animal models. The role of RNA-binding proteins in the induction of tissues' immunogenicity is increasingly recognized, but, the impact of the IGF2BPs family of proteins on the induction of innate and adaptive immune responses in cancer is not fully understood. Here we report that downregulation of IGF2BP1, 2, and 3 expression facilitates the expression of interferon beta-stimulated genes. IGF2BP1 has a greater effect on interferon beta and gamma signaling compared to IGF2BP2 and IGF2BP3 paralogs. We demonstrate that knockdown or knockout of IGF2BP1, 2, and 3 significantly potentiates inhibition of cell growth induced by IFNβ and IFNγ. Mouse melanoma cells with Igf2bp knockouts demonstrate increased expression of MHC I (H-2) and induce intracellular Ifn-γ expression in syngeneic T-lymphocytes . Increased immunogenicity, associated with Igf2bp1 inhibition, "inflames" mouse melanoma tumors microenvironment in SM1/C57BL/6 and SW1/C3H mouse models measured by a two-fold increase of NK cells and tumor-associated myeloid cells. Finally, we demonstrate that the efficiency of anti-PD1 immunotherapy in the mouse melanoma model is significantly more efficient in tumors that lack Igf2bp1 expression. Our retrospective data analysis of immunotherapies in human melanoma patients indicates that high levels of IGF2BP1 and IGF2BP3 are associated with resistance to immunotherapies and poor prognosis. In summary, our study provides evidence of the role of IGF2BP proteins in regulating tumor immunogenicity and establishes those RBPs as immunotherapeutic targets in cancer.
10.3389/fimmu.2023.1224516
Integrative genomic analyses of the RNA-binding protein, RNPC1, and its potential role in cancer prediction.
Ding Zhiming,Yang Hai-Wei,Xia Tian-Song,Wang Bo,Ding Qiang
International journal of molecular medicine
The RNA binding motif protein 38 (RBM38, also known as RNPC1) plays a pivotal role in regulating a wide range of biological processes, from cell proliferation and cell cycle arrest to cell myogenic differentiation. It was originally recognized as an oncogene, and was frequently found to be amplified in prostate, ovarian and colorectal cancer, chronic lymphocytic leukemia, colon carcinoma, esophageal cancer, dog lymphomas and breast cancer. In the present study, the complete RNPC1 gene was identified in a number of vertebrate genomes, suggesting that RNPC1 exists in all types of vertebrates, including fish, amphibians, birds and mammals. In the different genomes, the gene had a similar 4 exon/3 intron organization, and all the genetic loci were syntenically conserved. The phylogenetic tree demonstrated that the RNPC1 gene from the mammalian, bird, reptile and teleost lineage formed a species-specific cluster. A total of 34 functionally relevant single nucleotide polymorphisms (SNPs), including 14 SNPs causing missense mutations, 8 exonic splicing enhancer SNPs and 12 SNPs causing nonsense mutations, were identified in the human RNPC1 gene. RNPC1 was found to be expressed in bladder, blood, brain, breast, colorectal, eye, head and neck, lung, ovarian, skin and soft tissue cancer. In 14 of the 94 tests, an association between RNPC1 gene expression and cancer prognosis was observed. We found that the association between the expression of RNPC1 and prognosis varied in different types of cancer, and even in the same type of cancer from the different databases used. This suggests that the function of RNPC1 in these tumors may be multidimensional. The sex determining region Y (SRY)-box 5 (Sox5), runt-related transcription factor 3 (RUNX3), CCAAT displacement protein 1 (CUTL1), v-rel avian reticuloendotheliosis viral oncogene homolog (Rel)A, peroxisome proliferator-activated receptor γ isoform 2 (PPARγ2) and activating transcription factor 6 (ATF6) regulatory transcription factor binding sites were identified in the upstream (promoter) region of the RNPC1 gene, and may thus be involved in the effects of RNPC1 in tumors.
10.3892/ijmm.2015.2237
A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells.
Lee Sooncheol,Micalizzi Douglas,Truesdell Samuel S,Bukhari Syed I A,Boukhali Myriam,Lombardi-Story Jennifer,Kato Yasutaka,Choo Min-Kyung,Dey-Guha Ipsita,Ji Fei,Nicholson Benjamin T,Myers David T,Lee Dongjun,Mazzola Maria A,Raheja Radhika,Langenbucher Adam,Haradhvala Nicholas J,Lawrence Michael S,Gandhi Roopali,Tiedje Christopher,Diaz-Muñoz Manuel D,Sweetser David A,Sadreyev Ruslan,Sykes David,Haas Wilhelm,Haber Daniel A,Maheswaran Shyamala,Vasudevan Shobha
Genome biology
BACKGROUND:Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown. RESULTS:We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo. CONCLUSIONS:These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE-bearing mRNAs that promote chemoresistance. By disrupting this pathway, we develop an effective combination therapy against chemosurvival.
10.1186/s13059-020-1936-4
SIRT3, PP2A and TTP protein stability in the presence of TNF-α on vincristine-induced apoptosis of leukaemia cells.
Wang Liang-Jun,Chiou Jing-Ting,Lee Yuan-Chin,Huang Chia-Hui,Shi Yi-Jun,Chang Long-Sen
Journal of cellular and molecular medicine
The contribution of vincristine (VCR)-induced microtubule destabilization to evoke apoptosis in cancer cells remains to be resolved. Thus, we investigated the cytotoxic mechanism of VCR on U937 and HL-60 human leukaemia cell lines. We discovered that VCR treatment resulted in the up-regulation of TNF-α expression and activation of the death receptor pathway, which evoked apoptosis of U937 cells. Moreover, VCR induced microtubule destabilization and mitotic arrest. VCR treatment down-regulated SIRT3, and such down-regulation caused mitochondrial ROS to initiate phosphorylation of p38 MAPK. p38 MAPK suppressed MID1-modulated degradation of the protein phosphatase 2A (PP2A) catalytic subunit. The SIRT3-ROS-p38 MAPK-PP2A axis inhibited tristetraprolin (TTP)-controlled TNF-α mRNA degradation, consequently, up-regulating TNF-α expression. Restoration of SIRT3 and TTP expression, or inhibition of the ROS-p38 MAPK axis increased the survival of VCR-treated cells and repressed TNF-α up-regulation. In contrast to suppression of the ROS-p38 MAPK axis, overexpression of SIRT3 modestly inhibited the effect of VCR on microtubule destabilization and mitotic arrest in U937 cells. Apoptosis of HL-60 cells, similarly, went through the same pathway. Collectively, our data indicate that the SIRT3-ROS-p38 MAPK-PP2A-TTP axis modulates TNF-α expression, which triggers apoptosis of VCR-treated U937 and HL-60 cells. We also demonstrate that the apoptotic signalling is not affected by VCR-elicited microtubule destabilization.
10.1111/jcmm.14949
RNA-Binding Proteins in Acute Leukemias.
Schuschel Konstantin,Helwig Matthias,Hüttelmaier Stefan,Heckl Dirk,Klusmann Jan-Henning,Hoell Jessica I
International journal of molecular sciences
Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.
10.3390/ijms21103409
ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis.
Cell stem cell
Post-transcriptional adenosine-to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated. In blast crisis chronic myeloid leukemia (BC CML), we show that increased JAK2 signaling and BCR-ABL1 amplification activate ADAR1. In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1(E912A) mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs. Combined RNA sequencing, qRT-PCR, CLIP-ADAR1, and pri-let-7 mutagenesis data suggest that ADAR1 promotes LSC generation via let-7 pri-microRNA editing and LIN28B upregulation. A small-molecule tool compound antagonizes ADAR1's effect on LSC self-renewal in stromal co-cultures and restores let-7 biogenesis. Thus, ADAR1 activation represents a unique therapeutic vulnerability in LSCs with active JAK2 signaling.
10.1016/j.stem.2016.05.004
ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.
Jiang Qingfei,Crews Leslie A,Barrett Christian L,Chun Hye-Jung,Court Angela C,Isquith Jane M,Zipeto Maria A,Goff Daniel J,Minden Mark,Sadarangani Anil,Rusert Jessica M,Dao Kim-Hien T,Morris Sheldon R,Goldstein Lawrence S B,Marra Marco A,Frazer Kelly A,Jamieson Catriona H M
Proceedings of the National Academy of Sciences of the United States of America
The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
10.1073/pnas.1213021110
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.
,Ley Timothy J,Miller Christopher,Ding Li,Raphael Benjamin J,Mungall Andrew J,Robertson A Gordon,Hoadley Katherine,Triche Timothy J,Laird Peter W,Baty Jack D,Fulton Lucinda L,Fulton Robert,Heath Sharon E,Kalicki-Veizer Joelle,Kandoth Cyriac,Klco Jeffery M,Koboldt Daniel C,Kanchi Krishna-Latha,Kulkarni Shashikant,Lamprecht Tamara L,Larson David E,Lin Ling,Lu Charles,McLellan Michael D,McMichael Joshua F,Payton Jacqueline,Schmidt Heather,Spencer David H,Tomasson Michael H,Wallis John W,Wartman Lukas D,Watson Mark A,Welch John,Wendl Michael C,Ally Adrian,Balasundaram Miruna,Birol Inanc,Butterfield Yaron,Chiu Readman,Chu Andy,Chuah Eric,Chun Hye-Jung,Corbett Richard,Dhalla Noreen,Guin Ranabir,He An,Hirst Carrie,Hirst Martin,Holt Robert A,Jones Steven,Karsan Aly,Lee Darlene,Li Haiyan I,Marra Marco A,Mayo Michael,Moore Richard A,Mungall Karen,Parker Jeremy,Pleasance Erin,Plettner Patrick,Schein Jacquie,Stoll Dominik,Swanson Lucas,Tam Angela,Thiessen Nina,Varhol Richard,Wye Natasja,Zhao Yongjun,Gabriel Stacey,Getz Gad,Sougnez Carrie,Zou Lihua,Leiserson Mark D M,Vandin Fabio,Wu Hsin-Ta,Applebaum Frederick,Baylin Stephen B,Akbani Rehan,Broom Bradley M,Chen Ken,Motter Thomas C,Nguyen Khanh,Weinstein John N,Zhang Nianziang,Ferguson Martin L,Adams Christopher,Black Aaron,Bowen Jay,Gastier-Foster Julie,Grossman Thomas,Lichtenberg Tara,Wise Lisa,Davidsen Tanja,Demchok John A,Shaw Kenna R Mills,Sheth Margi,Sofia Heidi J,Yang Liming,Downing James R,Eley Greg
The New England journal of medicine
BACKGROUND:Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS:We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS:AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS:We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).
10.1056/NEJMoa1301689
RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation.
Palanichamy Jayanth Kumar,Tran Tiffany M,Howard Jonathan M,Contreras Jorge R,Fernando Thilini R,Sterne-Weiler Timothy,Katzman Sol,Toloue Masoud,Yan Weihong,Basso Giuseppe,Pigazzi Martina,Sanford Jeremy R,Rao Dinesh S
The Journal of clinical investigation
Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.
10.1172/JCI80046
Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis.
Eiring Anna M,Neviani Paolo,Santhanam Ramasamy,Oaks Joshua J,Chang Ji Suk,Notari Mario,Willis William,Gambacorti-Passerini Carlo,Volinia Stefano,Marcucci Guido,Caligiuri Michael A,Leone Gustavo W,Perrotti Danilo
Blood
Several RNA binding proteins (RBPs) have been implicated in the progression of chronic myelogenous leukemia (CML) from the indolent chronic phase to the aggressively fatal blast crisis. In the latter phase, expression and function of specific RBPs are aberrantly regulated at transcriptional or posttranslational levels by the constitutive kinase activity of the BCR/ABL oncoprotein. As a result, altered expression/function of RBPs leads to increased resistance to apoptotic stimuli, enhanced survival, growth advantage, and differentiation arrest of CD34+ progenitors from patients in CML blast crisis. Here, we identify the mRNAs bound to the hnRNP-A1, hnRNP-E2, hnRNP-K, and La/SSB RBPs in BCR/ABLtransformed myeloid cells. Interestingly, we found that the mRNA encoding the transcription factor E2F3 associates to hnRNP-A1 through a conserved binding site located in the E2F3 3' untranslated region (UTR). E2F3 levels were up-regulated in CML-BCCD34+ in a BCR/ABL kinase- and hnRNP-A1 shuttling-dependent manner. Moreover, by using shRNA-mediated E2F3 knock-down and BCR/ABL-transduced lineage-negative bone marrow cells from E2F3+/+ and E2F3-/- mice, we show that E2F3 expression is important for BCR/ABL clonogenic activity and in vivo leukemogenic potential. Thus, the complexity of the mRNA/RBP network, together with the discovery of E2F3 as an hnRNP-A1-regulated factor, outlines the relevant role played by RBPs in posttranscriptional regulation of CML development and progression.
10.1182/blood-2007-05-090472
Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
Nature communications
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
10.1038/s41467-019-10523-3
Review on circular RNAs and new insights into their roles in cancer.
Computational and structural biotechnology journal
Circular RNAs (circRNAs) are a very interesting class of conserved single-stranded RNA molecules derived from exonic or intronic sequences by precursor mRNA back-splicing. Unlike canonical linear RNAs, circRNAs form covalently closed, continuous stable loops without a 5'end cap and 3'end poly(A) tail, and therefore are resistant to exonuclease digestion. The majority of circRNAs are highly abundant, and conserved across different species with a tissue or developmental-stage-specific expression. circRNAs have been shown to play important roles as microRNA sponges, regulators of gene splicing and transcription, RNA-binding protein sponges and protein/peptide translators. Emerging evidence reveals that circRNAs function in various human diseases, particularly cancers, and may function as better predictive biomarkers and therapeutic targets for cancer treatment. In consideration of their potential clinical relevance, circRNAs have become a new research hotspot in the field of tumor pathology. In the present study, the current understanding of the biogenesis, characteristics, databases, research methods, biological functions subcellular distribution, epigenetic regulation, extracellular transport and degradation of circRNAs was discussed. In particular, the multiple databases and methods involved in circRNA research were first summarized, and the recent advances in determining the potential roles of circRNAs in tumor growth, migration and invasion, which render circRNAs better predictive biomarkers, were described. Furthermore, future perspectives for the clinical application of circRNAs in the management of patients with cancer were proposed, which could provide new insights into circRNAs in the future.
10.1016/j.csbj.2021.01.018
DNA- and RNA-Binding Proteins Linked Transcriptional Control and Alternative Splicing Together in a Two-Layer Regulatory Network System of Chronic Myeloid Leukemia.
Frontiers in molecular biosciences
DNA- and RNA-binding proteins (DRBPs) typically possess multiple functions to bind both DNA and RNA and regulate gene expression from more than one level. They are controllers for post-transcriptional processes, such as splicing, polyadenylation, transportation, translation, and degradation of RNA transcripts in eukaryotic organisms, as well as regulators on the transcriptional level. Although DRBPs are reported to play critical roles in various developmental processes and diseases, it is still unclear how they work with DNAs and RNAs simultaneously and regulate genes at the transcriptional and post-transcriptional levels. To investigate the functional mechanism of DRBPs, we collected data from a variety of databases and literature and identified 118 DRBPs, which function as both transcription factors (TFs) and splicing factors (SFs), thus called DRBP-SF. Extensive investigations were conducted on four DRBP-SFs that were highly expressed in chronic myeloid leukemia (CML), heterogeneous nuclear ribonucleoprotein K (HNRNPK), heterogeneous nuclear ribonucleoprotein L (HNRNPL), non-POU domain-containing octamer-binding protein (NONO), and TAR DNA-binding protein 43 (TARDBP). By integrating and analyzing ChIP-seq, CLIP-seq, RNA-seq, and shRNA-seq data in K562 using binding and expression target analysis and Statistical Utility for RBP Functions, we discovered a two-layer regulatory network system centered on these four DRBP-SFs and proposed three possible regulatory models where DRBP-SFs can connect transcriptional and alternative splicing regulatory networks cooperatively in CML. The exploration of the identified DRBP-SFs provides new ideas for studying DRBP and regulatory networks, holding promise for further mechanistic discoveries of the two-layer gene regulatory system that may play critical roles in the occurrence and development of CML.
10.3389/fmolb.2022.920492
Recognition sequence of a highly conserved DNA binding protein RBP-J kappa.
Tun T,Hamaguchi Y,Matsunami N,Furukawa T,Honjo T,Kawaichi M
Nucleic acids research
DNA binding specificity of the RBP-J kappa protein was extensively examined. The mouse RBP-J kappa protein was originally isolated as a nuclear protein binding to the J kappa type V(D)J recombination signal sequence which consisted of the conserved heptamer (CACTGTG) and nonamer (GGTTTTTGT) sequences separated by a 23-base pair spacer. Electrophoretic mobility shift assay using DNA probes with mutations in various parts of the J kappa recombination signal sequence showed that the RBP-J kappa protein recognized the sequence outside the recombination signal in addition to the heptamer but did not recognize the nonamer sequence and the spacer length at all. Database search identified the best naturally occurring binding motif (CACTGTGGGAACGG) for the RBP-J kappa protein in the promoter region of the m8 gene in the Enhancer of split gene cluster of Drosophila. The binding assay with a series of m8 motif mutants indicated that the protein recognized mostly the GTGGGAA sequence and also interacted weakly with ACT and CG sequences flanking this hepta-nucleotide. Oligonucleotides binding to the RBP-J kappa protein were enriched from a pool of synthetic oligonucleotides containing 20-base random sequences by the repeated electrophoretic mobility shift assay. The enriched oligomer shared a common sequence of CGTGGGAA. All these data indicate that the RBP-J kappa protein recognizes a unique core sequence of CGTGGGAA and does not bind to the V(D)J recombination signal without the flanking sequence.
10.1093/nar/22.6.965
RBP EIF2S2 Promotes Tumorigenesis and Progression by Regulating MYC-Mediated Inhibition via FHIT-Related Enhancers.
Zhang Jiwei,Li Shengli,Zhang Ling,Xu Juan,Song Mingxu,Shao Tingting,Huang Zhaohui,Li Yongsheng
Molecular therapy : the journal of the American Society of Gene Therapy
RNA-binding proteins (RBPs) play fundamental roles in cancer; however, we still lack knowledge about to what extent RBPs are dysregulated, as well as about perturbed signaling pathways in cancer. In this study, we integrated analysis of multidimensional data across >10,000 cancer patients and >1,000 cell lines. We identified a top candidate RBP: eukaryotic translation initiation factor 2 subunit beta (EIF2S2). EIF2S2 is highly expressed in tumors and is associated with malignant features as well as patient prognosis. Functional assays performed in cancer cells revealed that EIF2S2 promotes cancer cell proliferation, migration, and invasion in vitro as well as tumor growth and metastasis in vivo. Mechanistic investigations further demonstrated that EIF2S2 promotes tumorigenesis and progression by directly binding to a long non-coding RNA, LINC01600, which physically interacts with the MYC protein and increases its stability. Interestingly, we revealed that the EIF2S2-LINC01600-MYC axis can activate the Wnt/β-catenin pathway by inhibiting the activity of FHIT-related enhancers and FHIT expression. Finally, EIF2S2 knockdown combined with oxaliplatin treatment could be a potential combination therapy in cancer. Our integrated analysis provided detailed knowledge of the function of the EIF2S2-LINC01600-MYC axis, which will facilitate the development of rational combination therapies for cancer.
10.1016/j.ymthe.2020.02.004
RBP-J deficiency promoted the proliferation and differentiation of CD133-positive cells in both in vitro and in vivo studies.
The European journal of neuroscience
Although Notch signalling pathway could control the proliferation and differentiation of neural stem cells (NSCs), it is largely unknown about the effect of Notch signalling pathway on the neurogenesis of CD133-positive cells. By using the primary cultured ependymal cells and the transgenic mouse, we found that CD133 immunoreactivity was exclusively localized in the ependymal layer of ventricles; moreover, most CD133-positive cells were co-labelled with Nestin. In addition, recombination signal binding protein J (RBP-J), a key nuclear effector of Notch signalling pathway, was highly active in CD133-positive cells. CD133-positive cells can differentiate into the immature and mature neurons; in particular, the number of CD133-positive cells differentiating into the immature and mature neurons was significantly increased following the deficiency or interference of RBP-J in vivo or in vitro. By using real-time qPCR and Western blot, we found that RBP-J and Hes1 were downregulated, whereas Notch1 was upregulated in the expression levels of mRNAs and proteins following the deficiency or interference of RBP-J. These results demonstrated RBP-J deficiency promoted the proliferation and differentiation of CD133-positive cells. Therefore, we speculated that RBP-J could maintain CD133-positive cells in the characteristics of NSCs possibly by regulating Notch1/RBP-J/Hes1 pathway. It will provide a novel molecular insight into the function of RBP-J as well as facilitate a future investigation of CD133-positive cells with respect to their potential application in neurodegenerative disorder.
10.1111/ejn.15727
Identification of RNA-RBP Interactions in Subcellular Compartments by CLIP-Seq.
Methods in molecular biology (Clifton, N.J.)
Cross-linking immunoprecipitation and high-throughput sequencing (CLIP-seq) allows the identification of RNA targets bound by a specific RNA-binding protein (RBP) in in vivo and ex vivo experimental models with high specificity. Due to the little RNA yield obtained after cross-linking, immunoprecipitation, polyacrylamide gel electrophoresis, membrane transfer, and RNA extraction, CLIP-seq is usually performed from relatively large amounts of starting material, like cell lysates or tissue homogenates. However, RBP binding of its specific RNA targets depends on its subcellular localization, and a different set of RNAs may be bound by the same RBP within distinct subcellular sites. To uncover these RNA subsets, preparation of CLIP-seq libraries from specific subcellular compartments and comparison to CLIP-seq datasets from total lysates is necessary, yet there are currently no available protocols for this. Here we describe the adaptation of CLIP-seq to identify the specific RNA targets of an RBP (FUS) at a small subcompartment, that is, neuronal synapses, including subcompartment isolation, RBP-RNA complex enrichment, and upscaling steps.
10.1007/978-1-0716-1975-9_19
RBP-RNA interactions in the control of autoimmunity and autoinflammation.
Cell research
Autoimmunity and autoinflammation arise from aberrant immunological and inflammatory responses toward self-components, contributing to various autoimmune diseases and autoinflammatory diseases. RNA-binding proteins (RBPs) are essential for immune cell development and function, mainly via exerting post-transcriptional regulation of RNA metabolism and function. Functional dysregulation of RBPs and abnormities in RNA metabolism are closely associated with multiple autoimmune or autoinflammatory disorders. Distinct RBPs play critical roles in aberrant autoreactive inflammatory responses via orchestrating a complex regulatory network consisting of DNAs, RNAs and proteins within immune cells. In-depth characterizations of RBP-RNA interactomes during autoimmunity and autoinflammation will lead to a better understanding of autoimmune pathogenesis and facilitate the development of effective therapeutic strategies. In this review, we summarize and discuss the functions of RBP-RNA interactions in controlling aberrant autoimmune inflammation and their potential as biomarkers and therapeutic targets.
10.1038/s41422-022-00752-5
circRIP: an accurate tool for identifying circRNA-RBP interactions.
Briefings in bioinformatics
Circular ribonucleic acids (RNAs) (circRNAs) are formed by covalently linking the downstream splice donor and the upstream splice acceptor. One of the most important functions of circRNAs is mainly exerted through binding RNA-binding proteins (RBPs). However, there is no efficient algorithm for identifying genome-wide circRNA-RBP interactions. Here, we developed a unique algorithm, circRIP, for identifying circRNA-RBP interactions from RNA immunoprecipitation sequencing (RIP-Seq) data. A simulation test demonstrated the sensitivity and specificity of circRIP. By applying circRIP, we identified 95 IGF2BP3-binding circRNAs based on the IGF2BP3 RIP-Seq dataset. We further identified 2823 and 1333 circRNAs binding to >100 RBPs in K562 and HepG2 cell lines, respectively, based on enhanced cross-linking immunoprecipitation (eCLIP) data, demonstrating the significance to survey the potential interactions between circRNAs and RBPs. In this study, we provide an accurate and sensitive tool, circRIP (https://github.com/bioinfolabwhu/circRIP), to systematically identify RBP and circRNA interactions from RIP-Seq and eCLIP data, which can significantly benefit the research community for the functional exploration of circRNAs.
10.1093/bib/bbac186
Cancer the'RBP'eutics-RNA-binding proteins as therapeutic targets for cancer.
Mohibi Shakur,Chen Xinbin,Zhang Jin
Pharmacology & therapeutics
RNA-binding proteins (RBPs) play a critical role in the regulation of various RNA processes, including splicing, cleavage and polyadenylation, transport, translation and degradation of coding RNAs, non-coding RNAs and microRNAs. Recent studies indicate that RBPs not only play an instrumental role in normal cellular processes but have also emerged as major players in the development and spread of cancer. Herein, we review the current knowledge about RNA binding proteins and their role in tumorigenesis as well as the potential to target RBPs for cancer therapeutics.
10.1016/j.pharmthera.2019.07.001
Musashi-1-A Stemness RBP for Cancer Therapy?
Biology
The RNA-binding protein Musashi-1 (MSI1) promotes stemness during development and cancer. By controlling target mRNA turnover and translation, MSI1 is implicated in the regulation of cancer hallmarks such as cell cycle or Notch signaling. Thereby, the protein enhanced cancer growth and therapy resistance to standard regimes. Due to its specific expression pattern and diverse functions, MSI1 represents an interesting target for cancer therapy in the future. In this review we summarize previous findings on MSI1's implications in developmental processes of other organisms. We revisit MSI1's expression in a set of solid cancers, describe mechanistic details and implications in MSI1 associated cancer hallmark pathways and highlight current research in drug development identifying the first MSI1-directed inhibitors with anti-tumor activity.
10.3390/biology10050407