Integrative analysis of transcriptomic and clinical data uncovers the tumor suppressive activity of MITF in prostate cancer

Abstract

25The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of 26 transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, 27provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-28 annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to 29 prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor 30 (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further 31 interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and 32 unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, 33 at least in part, responsible for its tumor suppressive activity in prostate cancer. This evidence was 34 supported by the enhanced prognostic potential of a signature based on the concomitant alteration of 35 MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of 36 the potential of the bioinformatics screen of publicly available cancer patient databases as discovery 37 platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology. 38 39 have demonstrated that deregulation of gene expression is a key node for cancer pathogenesis and 48 progression (2-6). Prostate cancer (PCa) research exemplifies the effort in deciphering the genomics 49 and transcriptomics landscape of tumors, and extremely valuable data has been generated (7-13). In 50 spite of the public availability of these relevant data, they are still underexploited by the scientific 51 community to understand PCa biology. In this regard, the computational tools and dataset selection 52 strategies to carry out these studies are a bottleneck for the cancer research field. 53By combining integrated-bioinformatics screening of clinically relevant PCa datasets with in vivo and in 54 vitro molecular biology assays, we have recently described the metastasis suppressor activity of 55 Peroxisome proliferator-activated receptor γ (PPARγ) coactivator alpha (PGC1α) (14, 15). This 56 transcriptional coactivator is a major regulator of mitochondrial biogenesis and function, and has an 57 inherent capacity to integrate environmental signals and cellular energetic demands. This ability 58 empowers PGC1α to be a driver in shaping responses to metabolic stress during different physiologic 59 and tumorigenic processes (16). As might be expected due to its fundamental role in normal and cancer 60 scenarios, the regulation of PGC1α expression, from the genomic to the protein level, is complex and 61 dynamic (17). At the level of mRNA expression, one of the well-defined direct regulators of PGC1αis 62 the Microphthalmia-associated transcription factor (MITF) (18). 63MITF is a basic helix-loop-helix leucine zipper (bHLHZIP) transcription factor that regulates the 64 expression of lin...

HIRA loss transforms FH-deficient cells

“…The senescence assay was performed using the senescence β-Galactosidase staining kit from Cell Signaling Technology (#9860) following manufacturer instructions. BrdU staining was performed as previously described (34). For BrdU incorporation, cells were seeded on coverslips in 12-well plates and after 2 days, cells were incubated with 3 μg/mL BrdU (Sigma).…”