GSE169090
Inhibition of CDK9 activity compromises global splicing in prostate cancer cells
Cyclin-dependent kinase 9 (CDK9) phosphorylates RNA polymerase II to promote productive transcription elongation and the phosphorylation also regulates recruitment of the splicing machinery. Here we show that acute CDK9 inhibition affects splicing of thousands of mRNAs. CDK9 inhibition impairs global splicing and there is no evidence for a coordinated response between alternative splicing and the overall transcriptome. Alternative splicing is feature of aggressive prostate cancer (CRPC) and enables generation of an anti-androgen resistant version of a ligand-independent androgen receptor, AR-v7. We show that CDK9 inhibition compromises splicing of the androgen receptor (AR) mRNA due to the faulty utilization of alternative 3'splice site and introduction of premature stop codon. Consequently, this defective splicing results in the loss of AR and AR-v7 expression in models of CRPC. We show that CDK9 expression increases as PC cells develop CRPC-phenotype both in vitro and also in patient samples. Overall design: mRNA profiles of LNCaP cells after knockdown of OGT for 48 hours and treated with either DMSO or CDK inhibitor (0.5µM AT7519) for 4 hours prior to harvesting.