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 |
Journal | RNA Biol |
Pagination | 1-8 |
Date Published | 2021 Sep 30 |
ISSN | 1555-8584 |
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 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. |
DOI | 10.1080/15476286.2021.1983287 |
Alternate Journal | RNA Biol |
PubMed ID | 34592899 |
Related Faculty:
Massimo Loda, M.D.