Abstract
Abstract Emergence of constitutively active androgen receptor variant AR-V7 is associated with poor survival of castration-resistant prostate cancer (CRPC). AR-V7 can be generated by the inclusion of cryptic exon CE3 via alternative splicing, but the mechanism of AR-V7 activation remains elusive. Here, we show that histone lysine demethylase KDM4B promotes CRPC via generation of AR-V7. Genetic inactivation of KDM4B in CRPC cells suppressed xenograft growth and abolished tumor AR-V7 expression. Pharmacologic inhibition of KDM4B inhibited tumor growth and sensitized CRPC cells to current antiandrogen therapy. Mechanistically, KDM4B promotes AR-V7 as a trans-acting splicing factor and couples the spliceosome to the chromatin. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC. Citation Format: Zhi-Ping Liu. KDM4B promotes castration-resistant prostate cancer by regulating alternative splicing of the androgen receptor [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 A016.
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