Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation

Lingling Duan, Zhenhua Chen, Jun Lu, Yanping Liang, Ming Wang, Carlos M. Roggero, Qing Jun Zhang, Jason Gao, Yong Fang, Jiazheng Cao, Jian Lu, Hongwei Zhao, Andrew Dang, Rey Chen Pong, Elizabeth Hernandez, Chun Mien Chang, David T. Hoang, Jung Mo Ahn, Guanghua Xiao, Rui Tao WangKai Jiang Yu, Payal Kapur, Josep Rizo, Jer Tsong Hsieh, Junhang Luo, Zhi Ping Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)11623-11636
Number of pages14
JournalNucleic acids research
Volume47
Issue number22
DOIs
StatePublished - Dec 16 2019

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Duan, L., Chen, Z., Lu, J., Liang, Y., Wang, M., Roggero, C. M., Zhang, Q. J., Gao, J., Fang, Y., Cao, J., Lu, J., Zhao, H., Dang, A., Pong, R. C., Hernandez, E., Chang, C. M., Hoang, D. T., Ahn, J. M., Xiao, G., ... Liu, Z. P. (2019). Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation. Nucleic acids research, 47(22), 11623-11636. https://doi.org/10.1093/nar/gkz1004