Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer

Cell Reports

Michael Berk¹  Yoon-Mi Chung¹  Nima Sharifi¹  Hyun-Kyung Ko¹  Rohan Bareja²  Mark Rubin²  Andrea Sboner²  Belinda Willard³ 

[1] Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA;Institute for Precision Medicine, Weill-Cornell Medical Center, New York, NY 10065, USA;Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA;

关键词: prostate cancer;    metabolism;    androgens;    androgen receptor;    steroids;    enzymes;    drug resistance;    HSD17B4;    oncology;    splicing;   

DOI  :  10.1016/j.celrep.2017.12.081

来源: DOAJ

【 摘 要 】

Castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained testosterone and/or dihydrotestosterone to stimulate progression. 17β-Hydroxysteroid dehydrogenase type 4 (17βHSD4), encoded by HSD17B4, is thought to inactivate testosterone and dihydrotestosterone by converting them to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression increases in CRPC and predicts poor prognosis. Here, we show that, of five alternative splice forms, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast with other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients. Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulating androgen receptor (AR) and CRPC development. Our studies specifically implicate HSD17B4 isoform 2 loss in lethal prostate cancer.

【 授权许可】

Unknown