Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB
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Sang Eun Park1,7, Hye Jin Yi1, Nayoung Suh9, Yun-Yong Park2,5, Jae-Young Koh3,4,6, Seong-Yun Jeong1,2,5, Dong-Hyung Cho8, Choung-Soo Kim1,4,7, Jung Jin Hwang1,2,5
1Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea
2Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
3Department of Neurology, Asan Medical Center, Seoul, Korea
4Department of Urology, Asan Medical Center, Seoul, Korea
5Department of Convergence Medicine, University of Ulsan, College of Medicine, Seoul, Korea
6Neural Injury Research Lab, University of Ulsan, College of Medicine, Seoul, Korea
7Department of Urology, University of Ulsan, College of Medicine, Seoul, Korea
8Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Korea
9Department of Medicine Engineering, Soon Chun Hyang University, College of Medical Sciences, Asan, Korea
Jung Jin Hwang, e-mail: firstname.lastname@example.org
Choung-Soo Kim, e-mail: email@example.com
Keywords: EHMT2/G9a, histone methyltransferase, Beclin-1, autophagy, epigenetic regulation
Received: October 14, 2015 Accepted: April 16, 2016 Published: May 11, 2016
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-κB) 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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