Inverse regulation of DHT synthesis enzymes 5α-reductase types 1 and 2 by the androgen receptor in prostate cancer

37Citations
Citations of this article
42Readers
Mendeley users who have this article in their library.

Abstract

5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5a-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5a-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2.

Cite

CITATION STYLE

APA

Audet-Walsh, É., Yee, T., Tam, I. S., & Giguère, V. (2017). Inverse regulation of DHT synthesis enzymes 5α-reductase types 1 and 2 by the androgen receptor in prostate cancer. Endocrinology, 158(4), 1015–1021. https://doi.org/10.1210/en.2016-1926

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free