title: Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB.
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.
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Department of Urology, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yi
authors.affiliation: Department of Medicine Engineering, Soon Chun Hyang University, College of Medical Sciences, Asan, Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Convergence Medicine, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.affiliation: Department of Neurology, Asan Medical Center, Seoul, Korea.|Department of Urology, Asan Medical Center, Seoul, Korea.|Neural Injury Research Laboratory, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Convergence Medicine, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Korea.
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Department of Urology, Asan Medical Center, Seoul, Korea.|Department of Urology, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Choung-Soo
authors.initials: CS
authors.lastname: Kim
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Department of Convergence Medicine, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
mesh_terms: D001381:Azepines / Q000737:chemistry; D000071186:Beclin-1 / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D006649:Histocompatibility Antigens / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000737:chemistry; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D001381:Azepines; C518299:BIX 01294; D000071186:Beclin-1; D006649:Histocompatibility Antigens; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D011799:Quinazolines; D017382:Reactive Oxygen Species; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase
keywords: Beclin-1; EHMT2/G9a; autophagy; epigenetic regulation; histone methyltransferase