Combined inhibition of HDAC and DNMT1 induces p85α/MEKmediated cell cycle arrest by dual target inhibitor 208 in U937 cells  

作　　者：Yue Ren Qinsheng Sun Zigao Yuan Yuyang Jiang 

机构地区：[1]Department of Chemistry, Tsinghua University, Beijing 100084, China [2]State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China [3]National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, the Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China [4]School of Life Science, Tsinghua University, Beijing 100084, China [5]School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China

出　　处：《Chinese Chemical Letters》2019年第6期1233-1236,共4页中国化学快报（英文版）

基　　金：financial supports from Shenzhen Development and Reform Committee(No. 20151961);China Postdoctoral Science Foundation(No. 2018M631825);Department of Science and Technology of Guangdong Province (No. 2017B030314083)

摘　　要：Multiple histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have been developed for cancer therapy. However, the research on their mechanisms of action is not sophisticated enough. In this study, we reported a dual HDAC and DNMT inhibitor 208 and found it induced G1 cell cycle arrest and apoptosis in U937 cells. Proteome and bioinformatic analyses revealed that the combined inhibition of DNMT1 and HDAC by 208 affected the expression of a series of proteins involved in many biological processes. We observed that several proteins associated with G1 cell cycle arrest and apoptosis were down regulated after 208 treatment, including p85α, MEK, and CDK4, suggesting that 208 induces cell cycle arrest and apoptosis through the p85α/MEK-mediated pathway in U937 cells. Moreover, biological function analysis showed that the combined epigenetic inhibition influenced various processes, including the synthesis and processing of RNA, translation, protein transport, and DNA repair. These findings provide novel insight into the potential mechanisms of multifunctional epigenetic inhibitors, which supports their further improvement and development.Multiple histone deacetylase inhibitors(HDACi)and DNA methyltransferase inhibitors(DNMTi)have been develope d for cancer therapy.However,the research on their me chanisms of action is not sophisticated enough.In this study,we reported a dual HDAC and DNMT inhibitor 208 and found it induced G1 cell cycle arrest and apoptosis in U937 cells,Proteome and bioinformatic analyses revealed that the combined inhibition of DNMT1 and HDAC by 208 affected the expression of a series of proteins involved in many biological processes.We observed that several proteins associated with G1 cell cycle arrest and apoptosis were down regulated after 208 treatment,including p85α,MEK,and CDK4,suggesting that 208 induces cell cycle arrest and apoptosis through the p85 a/MEK-mediated pathway in U937 cells.Moreover,biological function analysis showed that the combined epigenetic inhibition influenced various processes,including the synthesis and processing of RNA,translation,protein transport,and DNA repair.These findings provide novel insight into the potential mechanisms of multifunctional epigenetic inhibitors,which supports their further improvement and development.

关 键 词：Proteomics Epigenetic INHIBITOR HDAC DNMT1 Cell cycle ARREST 

分 类 号：R96[医药卫生—药理学]