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

Dingxiao Zhang,Hsueh-Ping Chao,Xiaozhuo Liu,Yan Liu,Jianmin Wang,Silvia Buonamici,Song Liu,Amanda Tracz,Dean G Tang,Qiang Hu,Ping Zhu,Yibing Ji,Jason Kirk

doi:10.1038/s41467-020-15815-7

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.

Highlights

The role of dysregulation of mRNA alternative splicing (AS) in the development and progression of solid tumors remains to be defined
To determine the global AS dysregulation in prostate cancer (PCa) development and progression, we employed two AS mapping algorithms, rMATS14 and SUPPA15, to annotate RNA sequencing (RNA-seq) datasets (Supplementary Data 2) encompassing primary PCa (pri-PCa) and normal (N) prostate tissues[16], advanced PCa treated with ADT17,18, castration-resistant PCa (CRPC)-Ad19,20, and CRPCNE4,18 (Fig. 1a)
These results suggest that PCa development is accompanied by increased AS events, and that castration resistance and, in particular, metastasis are characterized by further significant increases in AS events

Summary

Introduction

The role of dysregulation of mRNA alternative splicing (AS) in the development and progression of solid tumors remains to be defined. We find that the severity of splicing dysregulation correlates with disease progression and establish intron retention as a hallmark of PCa stemness and aggressiveness. 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. Therapeutic targeting of mis-splicing by small molecules presents an innovative approach for treating hematological malignancies bearing core subunit mutations[8] and solid tumors driven by MYC10. Global analyses of aberrant AS landscape across many human cancer types, including PCa, have been reported using RNA-seq data in The Cancer Genome Atlas (TCGA)[9,12], but these studies generally overlooked PCa and only analyzed pri-PCa, leaving behind life-threatening mCRPC. We demonstrate that splicing misregulation can be exploited therapeutically for treating CRPC

Methods

Results

Conclusion