Inhibition of CDK9 activity compromises global splicing in prostate cancer cells

RNA Biol. 2021 Nov 12;18(sup2):722-729. doi: 10.1080/15476286.2021.1983287. Epub 2021 Sep 30.


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.

Keywords: Cyclin-dependent kinase 9; bioinformatics; o-glcnac transferase; prostate cancer; splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism
  • Enzyme Activation
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Oligonucleotides / genetics
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • RNA Interference
  • RNA Splicing*
  • RNA, Messenger / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Spliceosomes / metabolism


  • Oligonucleotides
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Receptors, Androgen
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9