Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation
Abstract
Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5′-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 24, 2019
- Source ID
- 10.1093/nar/gkz1004
Entities
People
- Andrew Dang
- Carlos M. Roggero
- Chun-mien Chang
- David T Hoang
- Elizabeth Hernandez
- Guanghua Xiao
- Hongwei Zhao
- Jason Gao
- Jer-Tsong Hsieh
- Jian Lu
- Jiazheng Cao
- Josep Rizo
- Jun Lü
- Jung-Mo Ahn
- Junhang Luo
- Kai-jiang Yu
- Lingling Duan
- Mingxun Wang
- Payal Kapur
- Qing-jun Zhang
- Rey-chen Pong
- Rui-tao Wang
- Yanping Liang
- Yong Fang
- Zhenhua Chen
- Zhi-ping Liu
Organizations
- Cancer Prevention and Research Institute of Texas
- Harbin Medical University
- National Institutes of Health
- National Natural Science Foundation of China
- Qingdao University
- Robert A. Welch Foundation
- Southern Medical University
- Sun Yat-sen University
- United States Department of Defense
- University of Texas Southwestern Medical Center
- University of Texas at Dallas