CDK8/19 inhibition induces premature G1/S transition and ATR-dependent cell death in prostate cancer cells
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Akito Nakamura1, Daisuke Nakata1, Yuichi Kakoi1, Mihoko Kunitomo1, Saomi Murai1, Shunsuke Ebara1, Akito Hata2 and Takahito Hara1
1Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
2Bio Molecular Research Laboratories, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Akito Nakamura, email: [email protected]
Keywords: CDK19; CDK8; prostate cancer; cell cycle; ATR
Received: March 26, 2017 Accepted: February 01, 2018 Published: February 06, 2018
The CDK8/19 kinase module comprises a subcomplex that interacts with the Mediator complex and regulates gene expression through phosphorylation of transcription factors and Mediator subunits. Mediator complex subunits have been increasingly implicated in cancer and other diseases. Although high expression of CDK8/19 has been demonstrated in prostate cancer, its function has not been thoroughly examined. Here we report that CDK8/19 modulates the gene expression of cell cycle regulators and thereby maintains the proper G1/S transition in prostate cancer cells. We show that highly selective CDK8/19 inhibitors exerted anti-proliferative activity in prostate cancer cells both in vitro and in vivo. In CDK8/19 inhibitor-sensitive prostate cancer cells, the compounds reduced the population of G1 phase cells and elevated that of S phase cells through the modulation of G1/S transition regulators at the level of mRNA expression. Furthermore, the premature G1/S transition induced a DNA damage response that was followed by ATR-dependent and caspase-independent cell death. These findings suggest a novel role of CDK8/19 in transcription-mediated cell cycle control, albeit with possible contribution of other proteins inhibited by the compounds. Our data provide a rationale for further investigation of CDK8/19 inhibitors as a new therapeutic approach to prostate cancer.
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