Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein

Supyong Hwang, Soyoung Kim, Kyungkon Kim, Jeonghun Yeom, Sojung Park, Inki Kim

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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, the one encoding the stress-response protein Ras-related GTPase C (RRAGC) was upregulated in all BIX-01294-treated HCC cell lines. We confirmed the regulatory roles of EHMT2 in RRAGC expression 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.

Original languageEnglish
Pages (from-to)576-581
Number of pages6
JournalBMB Reports
Issue number11
StatePublished - 2020

Bibliographical note

Funding Information:
This study was supported by a grant from the Bio and Medical Technology Development Program of the National Research Foundation (2017M3A9G7072719) and by the intramural research program of ASAN Institute for Life Sciences (2017-721). We thank the core facilities of HTS and CPC laboratory in the ConveRgence mEDIcine research center (CREDIT), and Asan Medical Center for the use of their shared equipment, services, and expertise.

Publisher Copyright:
© 2020 by the The Korean Society for Biochemistry and Molecular Biology


  • BIX-01294
  • EHMT2
  • ER stress
  • Epigenetics


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