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Euchromatin histone methyltransferase II (EHMT2) regulates the expression of Ras-related GTP binding C (RRAGC) protein
Supyong Hwang1 (Research worker), Soyoung Kim1 (Research worker), Kyungkon Kim1,2,3 (Professor), Jeonghun Yeom2 (Research worker), Sojung Park2 (Research worker), Inki Kim 1,2,3,* (Professor)
1Biomedical Research Center and 2Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea,
33Department of Convergence Medicine, , University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Dimethylation of the histone H3 protein at lysine residue 9 (H3K9) is mediated by euchromatin histone methyltransferase II (EHMT2), and results in transcriptional repression of target genes. Recently, chemical inhibition of EHMT2 was shown to induce various physiological outcomes including endoplasmic reticulum stress-associated genes transcription in cancer cells. To identify genes that are transcriptionally repressed by EHMT2 during apoptosis, and cell stress responses, we screened genes that are upregulated by BIX-01294, a chemical inhibitor of EHMT2. RNA sequencing analyses revealed 77 genes that were upregulated by BIX-01294 in all four hepatic cell carcinoma (HCC) cell lines. These included genes that have been implicated in apoptosis, the unfolded protein response (UPR) and others. Among these genes, that encoding the stress response protein Ras-related GTPase C (RRAGC) was upregulated in all BIX-01294-treated HCC cell lines. The regulatory roles of EHMT2 in RRAGC expression were confirmed in HCC cell lines using proteomic analyses, chromatin immune precipitation (ChIP) assay, and small guide RNA-mediated loss-of-function experiments. Upregulation of RRAGC was limited by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), suggesting that ROS are involved in EHMT2-mediated transcriptional regulation of stress response genes in HCC cells. Finally, combined treatment of cells with BIX-01294 and 5-Aza-cytidine induced greater upregulation of RRAGC protein expression. These findings suggest that EHMT2 suppresses expression of the RRAGC gene in a ROS-dependent manner, and imply that EHMT2 is a key regulator of stress responsive gene expression in liver cancer cells.
Abstract, Accepted Manuscript(in press) [Submitted on March 16, 2020, Accepted on June 16, 2020]
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