Inhibition of CDK9 activity compromises global splicing in prostate cancer cells.

Autor: Hu Q; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Poulose N; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK., Girmay S; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Helevä A; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Doultsinos D; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK., Gondane A; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Steele RE; PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, UK.; Breast Cancer Now Toby Robins Research Centre, the Institute of Cancer Research, London, UK., Liu X; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Loda M; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA.; The Broad Institute of Harvard and Mit, Cambridge, Massachusetts.; The New York Genome Center, New York, New York, USA., Liu S; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Tang DG; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Mills IG; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.; PCUK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology (CCRCB), Queen's University Belfast, Belfast, UK., Itkonen HM; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Jazyk: angličtina
Zdroj: RNA biology [RNA Biol] 2021 Nov 12; Vol. 18 (sup2), pp. 722-729. Date of Electronic Publication: 2021 Sep 30.
DOI: 10.1080/15476286.2021.1983287
Abstrakt: 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.
Databáze: MEDLINE