|Title||Inhibition of CDK9 activity compromises global splicing in prostate cancer cells.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Hu Q, Poulose N, Girmay S, Helevä A, Doultsinos D, Gondane A, Steele RE, Liu X, Loda M, Liu S, Tang D, Mills IG, Itkonen HM|
|Date Published||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 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.
|Alternate Journal||RNA Biol|
Massimo Loda, M.D.