Abstract A054: Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer

The development of castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained concentrations of testosterone and/or dihydrotestosterone, which stimulate tumor progression despite castration. 17βHSD4, encoded by HSD17B4, is an enzyme that is thought to inactive testosterone and dihydrotestosterone by way of conversion to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression is known to increase in CRPC and predict for poor prognosis. Here, we show that of 5 alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast to 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), stimulates PSA expression, and spurs the development of CRPC in xenograft models. Together, our studies specifically implicate HSD17B4 isoform 2 loss in the development of lethal prostate cancer. Citation Format: Hyun-Kyung Ko, Michael Berk, Yoon-Mi Chung, Belinda Willard, Rohan Bareja, Mark Rubin, Andrea Sboner, Nima Sharifi. Loss of an androgen-inactivating and isoform-specific HSD17B4 splice form enables emergence of castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A054.