Inhibition of CDK9 activity compromises global splicing in prostate cancer cells. Academic Article uri icon

Overview

abstract

  • Cyclin-dependent kinase 9 (CDK9) phosphorylates RNA polymerase II to promote productive transcription elongation. Here we show that short-term CDK9 inhibition affects the splicing of thousands of mRNAs. CDK9 inhibition impairs global splicing and there is no evidence for a coordinated response between the alternative splicing and the overall transcriptome. Alternative splicing is a feature of aggressive prostate cancer (CRPC) and enables the generation of the anti-androgen resistant version of the ligand-independent androgen receptor, AR-v7. We show that CDK9 inhibition results in the loss of AR and AR-v7 expression due to the defects in splicing, which sensitizes CRPC cells to androgen deprivation. Finally, we demonstrate that CDK9 expression increases as PC cells develop CRPC-phenotype both in vitro and also in patient samples. To conclude, here we show that CDK9 inhibition compromises splicing in PC cells, which can be capitalized on by targeting the PC-specific addiction androgen receptor.

publication date

  • September 30, 2021

Research

keywords

  • Cyclin-Dependent Kinase 9
  • Gene Expression Regulation, Neoplastic
  • Prostatic Neoplasms
  • Protein Kinase Inhibitors
  • RNA Splicing

Identity

PubMed Central ID

  • PMC8782174

Scopus Document Identifier

  • 85116356194

Digital Object Identifier (DOI)

  • 10.1080/15476286.2021.1983287

PubMed ID

  • 34592899

Additional Document Info

volume

  • 18

issue

  • sup2