Identification of transcription factor co-regulators that drive prostate cancer progression

• Published in: Scientific reports 2020-11, Vol.10 (1), p.20332-20332, Article 20332
• Main Authors: Siddappa, Manjunath, Wani, Sajad A., Long, Mark D., Leach, Damien A., Mathé, Ewy A., Bevan, Charlotte L., Campbell, Moray J.
• Format: Article
• Language: English
• Subjects: 631/337; 631/337/2019; 631/67; 631/67/69; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Cohort Studies; Copy number; Disease Progression; Disease-Free Survival; Down-Regulation - genetics; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene Regulatory Networks; Growth rate; Humanities and Social Sciences; Humans; Invasiveness; Male; multidisciplinary; Mutation; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Ribonucleic acid; RNA; RNA-Seq; Science; Science (multidisciplinary); Transcription factors; Transcription Factors - genetics; Transcriptome; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-77055-5

In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value