MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

• DOI: 10.1371/journal.pgen.1008540
• Publication Date: 2021-01-29T18:40:37Z
• Authors: Hannah Weber; Rachel Ruoff; Michael J. Garabe...
• Keywords: Male; 0301 basic medicine; Mediator Complex; Prostate; Prostatic Neoplasms; Acetylation; Androgen Antagonists; QH426-470; 16. Peace & justice; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Receptors, Androgen; Cell Line, Tumor; Genetics; Androgens; Humans; Promoter Regions, Genetic; Monoamine Oxidase; Research Article; Cell Proliferation; Signal Transduction; ets-Domain Protein Elk-1

Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence cells on androgen and receptor (AR). However, tumors become ADT-resistant, there need to understand mechanism. One possible mechanism upregulation AR co-regulators, although only handful have been definitively linked disease. We previously identified Mediator subunit MED19 as an co-regulator, reported that depletion inhibits transcriptional activity growth androgen-insensitive LNCaP-abl cells. Therefore, we proposed would promote drive androgen-independent growth. Here, show stable overexpression in androgen-dependent LNCaP promotes under conditions deprivation. To delineate mechanism, determined transcriptomes cistromes control MED19-overexpressing also examined genome-wide H3K27 acetylation. selectively alters occupancy, acetylation, gene expression. Under deprivation, genes regulated by correspond ELK1, transcription factor binds N-terminus induce select target expression proliferation, genomic sites occupied are enriched for motifs associated with ELK1. Strikingly, upregulates monoamine oxidase A (MAOA), MAOA reduces occupy promoter, enhancing occupancy Furthermore, increases ELK1 at This suggests cooperates regulate acetylation MAOA, upregulating its driving independence study provides important insight into mechanisms cell low androgen, underscores importance MED19-MAOA axis this process.