MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis

被引：85

作者：

Tu, William B. ^{[1
,2
]}

Shiah, Yu-Jia ^{[3
]}

Lourenco, Corey ^{[1
,2
]}

Mullen, Peter J. ^{[1
]}

Dingar, Dharmendra ^{[1
]}

Redel, Cornelia ^{[1
,2
]}

Tamachi, Aaliya ^{[1
]}

Ba-Alawi, Wail ^{[1
,2
]}

Aman, Ahmed ^{[4
]}

Al-awar, Rima ^{[4
,5
]}

Cescon, David W. ^{[1
,6
]}

Haibe-Kains, Benjamin ^{[1
,2
]}

Arrowsmith, Cheryl H. ^{[1
,2
,7
]}

Raught, Brian ^{[1
,2
]}

Boutros, Paul C. ^{[2
,5
]}

Penn, Linda Z. ^{[1
,2
]}

机构：

[1] Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[2] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[3] Ontario Inst Canc Res, Informat & Biocomp Program, Toronto, ON M5G 0A3, Canada

[4] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3, Canada

[5] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[6] Univ Toronto, Dept Med, Div Med Oncol & Hematol, Toronto, ON M5G 2C4, Canada

[7] Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

来源：

CANCER CELL | 2018年 / 34卷 / 04期

基金：

英国惠康基金; 巴西圣保罗研究基金会; 加拿大健康研究院; 加拿大创新基金会;

关键词：

HUMAN BREAST-CANCER; LARGE GENE LISTS; C-MYC; HUMAN GENOME; INTEGRATIVE ANALYSIS; EXPRESSION PROFILES; TUMOR-SUPPRESSOR; CHEMICAL PROBE; IN-VIVO; BOX-II;

D O I：

10.1016/j.ccell.2018.09.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MYC is an oncogenic driver that regulates transcriptional activation and repression. Surprisingly, mechanisms by which MYC promotes malignant transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression. By identifying the MYC box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. Across breast cancer cell lines, the anti-proliferative response to G9a pharmacological inhibition correlates with MYC sensitivity and gene signatures. Consistently, genetically depleting G9a in vivo suppresses MYC-dependent tumor growth. These findings unveil G9a as an epigenetic regulator of MYC transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.

引用

页码：579 / +

页数：25

共 50 条

[31] 15-hydroxyprostaglandin Dehydrogenase is Regulated by Histone Methyltransferase G9a in Cholangiocarcinoma
Zhang, Jinqiang
Chen, Weina
Han, Chang
Song, Kyoungsub
Ma, Wenbo
Wu, Tong
FASEB JOURNAL, 2019, 33
[32] Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a
Lei, Wenjing
Long, Yanjun
Li, Shuang
Liu, Ze
Zhu, Fengxin
Hou, Fan Fan
Nie, Jing
PLOS ONE, 2015, 10 (07):
[33] Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity
Maze, Ian
Covington, Herbert E., III
Dietz, David M.
LaPlant, Quincey
Renthal, William
Russo, Scott J.
Mechanic, Max
Mouzon, Ezekiell
Neve, Rachael L.
Haggarty, Stephen J.
Ren, Yanhua
Sampath, Srihari C.
Hurd, Yasmin L.
Greengard, Paul
Tarakhovsky, Alexander
Schaefer, Anne
Nestler, Eric J.
SCIENCE, 2010, 327 (5962) : 213 - 216
[34] Protein lysine methyltransferase G9a acts on non-histone targets
Philipp Rathert
Arunkumar Dhayalan
Marie Murakami
Xing Zhang
Raluca Tamas
Renata Jurkowska
Yasuhiko Komatsu
Yoichi Shinkai
Xiaodong Cheng
Albert Jeltsch
Nature Chemical Biology, 2008, 4 : 344 - 346
[35] Dual inhibition of DNA methyltransferase 1 and the histone methyltransferase G9a as a new therapeutic strategy in hepatoblastoma
Fernandez-Barrena, Maite G.
Claveria-Cabello, Alex
Colyn, Leticia
Carrillo, Juan
Oyarzabal, Julen
Sangro, Bruno
Sancho-Bru, Pau
Cairo, Stefano
Arechederra, Maria
Armengol, Carolina
Berasain, Carmen
Avila, Matias A.
JOURNAL OF HEPATOLOGY, 2020, 73 : S16 - S16
[36] Pharmacological and transcriptional inhibition of the G9a histone methyltransferase suppresses proliferation and modulates redox homeostasis in human microvascular endothelial cells
Wojtala, Martyna
Macierzynska-Piotrowska, Ewa
Rybaczek, Dorota
Pirola, Luciano
Balcerczyk, Aneta
PHARMACOLOGICAL RESEARCH, 2018, 128 : 252 - 263
[37] Total Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory Activity
Iwasa, Eriko
Hamashima, Yoshitaka
Fujishiro, Shinya
Higuchi, Eisuke
Ito, Akihiro
Yoshida, Minoru
Sodeoka, Mikiko
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2010, 132 (12) : 4078 - +
[38] Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma
Yokoyama, Masayuki
Chiba, Tetsuhiro
Zen, Yoh
Oshima, Motohiko
Kusakabe, Yuko
Noguchi, Yoshiko
Yuki, Kaori
Koide, Shuhei
Tara, Shiro
Saraya, Atsunori
Aoyama, Kazumasa
Mimura, Naoya
Miyagi, Satoru
Inoue, Masanori
Wakamatsu, Toru
Saito, Tomoko
Ogasawara, Sadahisa
Suzuki, Eiichiro
Ooka, Yoshihiko
Tawada, Akinobu
Otsuka, Masayuki
Miyazaki, Masaru
Yokosuka, Osamu
Iwama, Atsushi
ONCOTARGET, 2017, 8 (13) : 21315 - 21326
[39] Delineating the pathological roles and molecular functions of histone methyltransferase G9a in hepatocellular carcinoma
Wei, Lei
Tsang, Felice Ho-Ching
Au, Sandy Leung-Kuen
Lee, Joyce
Wong, Carmen
Ng, Irene Oi-Lin
Wong, Chun-Ming
CANCER RESEARCH, 2016, 76
[40] Epigenetic regulation of starvation-induced autophagy in Drosophila by histone methyltransferase G9a
Phan Nguyen Thuy An
Kouhei Shimaji
Ryo Tanaka
Hideki Yoshida
Hiroshi Kimura
Eiichiro Fukusaki
Masamitsu Yamaguchi
Scientific Reports, 7

← 1 2 3 4 5 →