Inhibition of CDK9 activity compromises global splicing in prostate cancer cells

Qiang Hu, Ninu Poulose, Samuel Girmay, Alma Heleva, Dimitrios Doultsinos, Aishwarya Gondane, Rebecca E. Steele, Xiaozhuo Liu, Massimo Loda, Song Liu, Dean Tang, Ian G. Mills, Harri M. Itkonen*

*Tämän työn vastaava kirjoittaja

Tutkimustuotos: LehtiartikkeliArticleScientificvertaisarvioitu

Abstrakti

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.

AlkuperäiskieliEnglanti
Sivut722-729
Sivumäärä8
JulkaisuRNA BIOLOGY
Vuosikerta18
DOI - pysyväislinkit
TilaJulkaistu - 12 marrask. 2021
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

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