The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

Biochemistry and Molecular Biology Department University of the Basque Country P O Box 644 48080 Bilbao Spain

CIBERONC Madrid Spain

CIC bioGUNE Bizkaia Technology Park 801ª bld 48160 Derio Bizkaia Spain

CLIP Childhood Leukaemia Investigation Dept of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Basurto University Hospital 48013 Bilbao Spain

Vascular Signalling Laboratory Institut d´Investigació Biomèdica de Bellvitge Gran Via de l'Hospitalet 199 203 Barcelona Spain

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