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

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.

Cell reports. 2018 Jan 16 [Epub]

Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Institute for Precision Medicine, Weill-Cornell Medical Center, New York, NY 10065, USA., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: .

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