MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen
Autoři:
Hannah Weber aff001; Rachel Ruoff aff001; Michael J. Garabedian aff001
Působiště autorů:
Departments of Microbiology and Urology, New York University School of Medicine, New York, New York, United States of America
aff001
Vyšlo v časopise:
MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen. PLoS Genet 17(1): e1008540. doi:10.1371/journal.pgen.1008540
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008540
Souhrn
Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19-overexpressing LNCaP cells. We also examined genome-wide H3K27 acetylation. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 correspond to genes regulated by ELK1, a transcription factor that binds the AR N-terminus to induce select AR target gene expression and proliferation, and genomic sites occupied by MED19 and AR are enriched for motifs associated with ELK1. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.
Klíčová slova:
Prostate cancer – Acetylation – Androgens – Ethanol – Gene expression – Small interfering RNA – Transcription factors – Transcriptional control
Zdroje
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