2. Academic Validation
  3. Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB

Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB

  • Oncotarget. 2016 Jun 28;7(26):39796-39808. doi: 10.18632/oncotarget.9290.
Sang Eun Park 1 2,  Hye Jin Yi 1,  Nayoung Suh 3,  Yun-Yong Park 4 5,  Jae-Young Koh 6 7 8,  Seong-Yun Jeong 1 4 5,  Dong-Hyung Cho 9,  Choung-Soo Kim 1 7 2,  Jung Jin Hwang 1 4 5
Affiliations

Affiliations

  • 1 Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
  • 2 Department of Urology, University of Ulsan, College of Medicine, Seoul, Korea.
  • 3 Department of Medicine Engineering, Soon Chun Hyang University, College of Medical Sciences, Asan, Korea.
  • 4 Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
  • 5 Department of Convergence Medicine, University of Ulsan, College of Medicine, Seoul, Korea.
  • 6 Department of Neurology, Asan Medical Center, Seoul, Korea.
  • 7 Department of Urology, Asan Medical Center, Seoul, Korea.
  • 8 Neural Injury Research Laboratory, University of Ulsan, College of Medicine, Seoul, Korea.
  • 9 Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Korea.
PMID: 27174920 DOI: 10.18632/oncotarget.9290
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-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.

Keywords

Beclin-1; EHMT2/G9a; autophagy; epigenetic regulation; histone methyltransferase.

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