Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Nov 21

PMID 30454645

Citations 115

Authors

Hanghang Zhang

Somnath Pandey

Meghan Travers

Hongxing Sun

George Morton

Jozef Madzo

Woonbok Chung

Jittasak Khowsathit

Oscar Perez-Leal

Carlos A Barrero

Carmen Merali

Yasuyuki Okamoto

Takahiro Sato

Joshua Pan

Judit Garriga

Natarajan V Bhanu

Johayra Simithy

Bela Patel

Jian Huang

Noel J-M Raynal

Benjamin A Garcia

Marlene A Jacobson

Cigall Kadoch

Salim Merali

Yi Zhang

Wayne Childers

Magid Abou-Gharbia

John Karanicolas

Stephen B Baylin

Cynthia A Zahnow

Jaroslav Jelinek

Xavier Grana

Jean-Pierre J Issa

Affiliations

Soon will be listed here.

Abstract

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

Citing Articles

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