Intron retention is a hallmark and spliceosome represents a therapeutic vulnerability in aggressive prostate cancer

Dingxiao Zhang (), Qiang Hu, Xiaozhuo Liu, Yibing Ji, Hsueh-Ping Chao, Yan Liu, Amanda Tracz, Jason Kirk, Silvia Buonamici, Ping Zhu, Jianmin Wang, Song Liu () and Dean G. Tang ()
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Dingxiao Zhang: Roswell Park Comprehensive Cancer Center
Qiang Hu: Roswell Park Comprehensive Cancer Center
Xiaozhuo Liu: Roswell Park Comprehensive Cancer Center
Yibing Ji: Roswell Park Comprehensive Cancer Center
Hsueh-Ping Chao: University of Texas MD Anderson Cancer Center
Yan Liu: Huazhong Agricultural University
Amanda Tracz: Roswell Park Comprehensive Cancer Center
Jason Kirk: Roswell Park Comprehensive Cancer Center
Silvia Buonamici: H3 Biomedicine, Inc.
Ping Zhu: H3 Biomedicine, Inc.
Jianmin Wang: Roswell Park Comprehensive Cancer Center
Song Liu: Roswell Park Comprehensive Cancer Center
Dean G. Tang: Roswell Park Comprehensive Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract The role of dysregulation of mRNA alternative splicing (AS) in the development and progression of solid tumors remains to be defined. Here we describe the first comprehensive AS landscape in the spectrum of human prostate cancer (PCa) evolution. We find that the severity of splicing dysregulation correlates with disease progression and establish intron retention as a hallmark of PCa stemness and aggressiveness. Systematic interrogation of 274 splicing-regulatory genes (SRGs) uncovers prevalent genomic copy number variations (CNVs), leading to mis-expression of ~68% of SRGs during PCa development and progression. Consequently, many SRGs are prognostic. Surprisingly, androgen receptor controls a splicing program distinct from its transcriptional regulation. The spliceosome modulator, E7107, reverses cancer aggressiveness and inhibits castration-resistant PCa (CRPC) in xenograft and autochthonous PCa models. Altogether, our studies establish aberrant AS landscape caused by dysregulated SRGs as a hallmark of PCa aggressiveness and the spliceosome as a therapeutic vulnerability for CRPC.

Date: 2020
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DOI: 10.1038/s41467-020-15815-7

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