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

Nat Commun. 2020 Apr 29;11(1):2089. doi: 10.1038/s41467-020-15815-7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cohort Studies
  • Disease Progression
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Epoxy Compounds / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Introns / genetics*
  • Kaplan-Meier Estimate
  • Macrolides / pharmacology
  • Male
  • Mice
  • Molecular Targeted Therapy
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Prognosis
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Spliceosomes / metabolism*
  • Transcription, Genetic / drug effects


  • E 7107
  • Epoxy Compounds
  • Macrolides