EZH2 inhibitors abrogate upregulation of trimethylation of H3K27 by CDK9 inhibitors and potentiate its activity against diffuse large B-cell lymphoma
Shao Xie,
Fan Wei,
Yi-ming Sun,
Ying-lei Gao,
Lu-lu Pan,
Min-jia Tan,
Shu-dong Wang,
Jian Ding,
Yi Chen
Affiliations
Shao Xie
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;Key Laboratory of Breast Cancer, and Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China
Fan Wei
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;University of Chinese Academy of Sciences, Beijing, China
Yi-ming Sun
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Ying-lei Gao
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Lu-lu Pan
University of Chinese Academy of Sciences, Beijing, China;Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica and Chinese Academy of Sciences, Shanghai, China
Min-jia Tan
Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica and Chinese Academy of Sciences, Shanghai, China
Shu-dong Wang
Centre for Drug Discovery and Development, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, Adelaide, Australia
Jian Ding
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Yi Chen
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research and Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Aberrant expression of CDK9/cyclin T1 has been found in diffuse large B-cell lymphoma (DLBCL), and suggests that CDK9 is a potential therapeutic target for DLBCL. Here, we firstly demonstrated that CDKI-73, a novel cyclin-dependent kinases (CDK) inhibitor, potently blocks CDK9, triggered apoptosis and dramatically repressed DLBCL cell growth owing to CDK9 inhibition. CDK9 inhibitors specifically elevated the trimethylation of H3K27, which we speculate was due to reduced expression of JMJD3/UTX. Considering the important role of the trimethylation of H3K27 in tumor progression, the synergistic effect of the combination therapy of CDK9 inhibitors with EZH2 inhibitors was investigated. EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited DLBCL and other solid tumors growth in vitro and in vivo. These findings provide a rational basis for the application of CDK9 inhibitors in combination with EZH2 inhibitors in clinical trials.
