Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-kappa B
- Authors
- Park, Sang Eun; Yi, Hye Jin; Suh, Nayoung; Park, Yun-Yong; Koh, Jae-Young; Jeong, Seong-Yun; Cho, Dong-Hyung; Kim, Choung-Soo; Hwang, Jung Jin
- Issue Date
- 28-Jun-2016
- Publisher
- Impact Journals
- Keywords
- EHMT2/G9a; histone methyltransferase; Beclin-1; autophagy; epigenetic regulation
- Citation
- Oncotarget, v.7, no.26, pp 39796 - 39808
- Pages
- 13
- Journal Title
- Oncotarget
- Volume
- 7
- Number
- 26
- Start Page
- 39796
- End Page
- 39808
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/9010
- DOI
- 10.18632/oncotarget.9290
- ISSN
- 1949-2553
- Abstract
- We previously reported that BIX-01294 (BIX), a small molecular inhibitor of euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a), induces reactive oxygen species (ROS)-dependent autophagy in MCF-7 cells. Herein, we analyzed the epigenetic mechanism that regulates the transcription of Beclin-1, a tumor suppressor and an autophagy-related gene (ATG). Inhibition of EHMT2 reduced dimethylation of lysine 9 on histone H3 (H3K9me2) and dissociated EHMT2 and H3K9me2 from the promoter of Beclin-1. To this promoter, RNA polymerase II and nuclear factor kappa B (NF-kappa B) were recruited in a ROS-dependent manner, resulting in transcriptional activation. Moreover, treatment with BIX reversed the suppression of Beclin-1 by the cooperative action of EHMT2 and DNA methyltransferase 1 (DNMT1). Accordingly, a combination treatment with BIX and 5-Aza-2'-deoxycytidine (5-Aza-Cd), a DNMT1 inhibitor, exerted a synergistic effect on Beclin-1 expression. Importantly, high levels of EHMT2 expression showed a significant association with low levels of Beclin-1 expression, which was related to a poor prognosis. These findings suggest that EHMT2 can directly repress Beclin-1 and that the inhibition of EHMT2 may be a useful therapeutic approach for cancer prevention by activating autophagy.
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Collections - College of Medical Sciences > Department of Pharmaceutical Engineering > 1. Journal Articles
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