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

Abstract

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.