期刊文献

Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer 收藏

组蛋白 - 赖氨酸N-甲基转移酶EHMT2（G9A）抑制作用可缓解MYC驱动的肝癌的肿瘤性
原文求助 发布源
作者
Dexter Kai Hao Thng[1];Lissa Hooi[1];Clarissa Chin Min Toh[1];Jhin Jieh Lim[1];Deepa Rajagopalan[1];Imran Qamar Charles Syariff[2];Zher Min Tan[2];Masturah Bte Mohd Abdul Rashid[3];Lei Zhou[4];Alfred Wei Chieh Kow[5];Glenn Kunnath Bonney[5];Brian Kim Poh Goh[6];Juinn Huar Kam[6];Sudhakar Jha[1];Yock Young Dan[4];Pierce Kah Hoe Chow[6];Tan Boon Toh[7];Edward Kai-Hua Chow[1]
作者单位
[1]Cancer Science Institute of Singapore National University of Singapore Singapore Singapore;[2]Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore;[3]KYAN Therapeutics Singapore Singapore;[4]Department of Medicine, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore;[5]Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, University Surgical Cluster National University Health System Singapore Singapore;[6]Department of Hepatopancreatobiliary (HPB) and Transplant Surgery Singapore General Hospital and National Cancer Centre Singapore Singapore Singapore;[7]The N.1 Institute for Health (N.1) National University of Singapore Singapore Singapore
关键词
epigenetics;G9a;HCC;Myc
关键词译文
表观遗传学; g9a; hcc; myc
发布日期
10 March 2023
页码
2275-2294
DOI
10.1002/1878-0261.13417
来源信息
Molecular Oncology ISSN：1574-7891, 2023年, 17卷, 11期, 2275-2294页
摘要
Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c-Myc interacts with G9a in HCC and cooperates to regulate c-Myc-dependent gene repression. In addition, G9a stabilises c-Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic-lethal target of c-Myc, CDK9, demonstrates strong efficacy in patient-derived avatars of Myc-driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc-driven hepatic tumours.
摘要译文
肝细胞癌（HCC）是世界上第三个最致命和第六大癌症。组蛋白赖氨酸N-甲基转移酶EHMT2（也称为G9A）是一种组蛋白甲基转移酶，经常在包括HCC在内的许多癌症类型中过表达。我们表明，MYC驱动的肝肿瘤具有独特的H3K9甲基化模式，并具有相应的G9A过表达。在我们的C-MYC阳性HCC患者衍生的异种移植物中进一步观察到了G9A增加的现象。更重要的是，我们表明，C-MYC和G9A表达水平较高的HCC患者的生存期限较差，中位生存月份。我们证明了C-MYC与HCC中的G9A相互作用，并合作以调节C-MYC依赖性基因抑制。此外，G9A稳定C-MYC以促进癌症的发展，从而有助于HCC的生长和侵入性能力。此外，c-Myc的G9A与合成致命靶标之间的联合疗法CDK9表现出在MYC驱动的HCC的患者衍生的化身中的强大功效。我们的工作表明，针对G9A的靶向可能被证明是MYC驱动的肝癌的潜在治疗途径。这将提高我们对侵袭性肿瘤起始的潜在表观遗传机制的理解，并改善MYC驱动的肝肿瘤的治疗和诊断选择。
Dexter Kai Hao Thng[1];Lissa Hooi[1];Clarissa Chin Min Toh[1];Jhin Jieh Lim[1];Deepa Rajagopalan[1];Imran Qamar Charles Syariff[2];Zher Min Tan[2];Masturah Bte Mohd Abdul Rashid[3];Lei Zhou[4];Alfred Wei Chieh Kow[5];Glenn Kunnath Bonney[5];Brian Kim Poh Goh[6];Juinn Huar Kam[6];Sudhakar Jha[1];Yock Young Dan[4];Pierce Kah Hoe Chow[6];Tan Boon Toh[7];Edward Kai-Hua Chow[1]. Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer[J]. Molecular Oncology, 2023,17(11): 2275-2294