Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer death worldwide. Hence, new therapeutic agents are urgently needed to manage colorectal cancer effectively. The epigenetic abnormalities of chromatin drive the initiation and progression of human cancers. Therefore, DNA methyltransferase and histone deacetylase inhibitors have been developed for clinical use, but no inhibitors of histone methyltransferase are under development for human cancer therapy. H3K9 methyltransferase G9a/G9a-like protein (GLP) is overexpressed in various human cancers, and its knockdown inhibits cancer cell growth, suggesting the cancer-suppressing potential of G9a/GLP inhibitors. UNC0642 is a potent and selective G9a/GLP inhibitor that suppresses breast cancer cell survival and tumorigenesis. In this study, we first tested the anticancer activity of UNC0642 in CRC in vitro and in the mouse xenograft model and further explored the underlying molecular mechanism. We found that UNC0642 inhibited CRC cell proliferation, induced G2/M-phase cell cycle arrest, increased reactive oxygen species level and expression of growth arrest– and DNA damage–inducible genes (GADD), activated p38, and JNK/MAPK signaling pathway. The findings of this study provided new evidence for exploring the potential of UNC0642 for tumor suppressor drug development and might help further explore the biological functions of G9a/GLP in CRC.