Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53

被引：133

作者：

Fei, Qi ^{[1
]}

Shang, Ke ^{[1
]}

Zhang, Jianhua ^{[1
]}

Chuai, Shannon ^{[1
]}

Kong, Desheng ^{[1
]}

Zhou, Tianlun ^{[1
]}

Fu, Shijun ^{[1
]}

Liang, Ying ^{[1
]}

Li, Chong ^{[1
]}

Chen, Zhi ^{[1
]}

Zhao, Yuan ^{[1
]}

Yu, Zhengtian ^{[1
]}

Huang, Zheng ^{[1
]}

Hu, Min ^{[1
]}

Ying, Haiyan ^{[1
]}

Chen, Zhui ^{[1
]}

Zhang, Yun ^{[1
]}

Xing, Feng ^{[1
]}

Zhu, Jidong ^{[1
]}

Xu, Haiyan ^{[1
]}

Zhao, Kehao ^{[1
]}

Lu, Chris ^{[1
]}

Atadja, Peter ^{[1
]}

Xiao, Zhi-Xiong ^{[2
]}

Li, En ^{[1
]}

Shou, Jianyong ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Shanghai 201203, Peoples R China

[2] Sichuan Univ, Coll Life Sci, Chengdu 610064, Peoples R China

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

TUMOR-SUPPRESSOR GENE; HEPATOCELLULAR-CARCINOMA; MUTANT P53; GAIN; ESET; ACETYLATION; REPRESSION; MUTATIONS; MELANOMA; LYSINE-9;

D O I：

10.1038/ncomms9651

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

SETDB1 is a histone H3K9 methyltransferase that has a critical role in early development. It is located within a melanoma susceptibility locus and facilitates melanoma formation. However, the mechanism by which SETDB1 regulates tumorigenesis remains unknown. Here we report the molecular interplay between SETDB1 and the well-known hotspot gain-of-function (GOF) TP53 R249S mutation. We show that in hepatocellular carcinoma (HCC) SETDB1 is overexpressed with moderate copy number gain, and GOF TP53 mutations including R249S associate with this overexpression. Inactivation of SETDB1 in HCC cell lines bearing the R249S mutation suppresses cell growth. The TP53 mutation status renders cancer cells dependent on SETDB1. Moreover, SETDB1 forms a complex with p53 and catalyses p53K370 di-methylation. SETDB1 attenuation reduces the p53K370me2 level, which subsequently leads to increased recognition and degradation of p53 by MDM2. Together, we provide both genetic and biochemical evidence for a mechanism by which SETDB1 regulates cancer cell growth via methylation of p53.

引用

页数：12

共 42 条

[1] AFLATOXIN-B(1) INDUCES THE TRANSVERSION OF G-]T IN CODON 249 OF THE P53 TUMOR-SUPPRESSOR GENE IN HUMAN HEPATOCYTES [J].

AGUILAR, F ;

HUSSAIN, SP ;

CERUTTI, P .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (18) :8586-8590

[2] CARCINOGENS ARE MUTAGENS - SIMPLE TEST SYSTEM COMBINING LIVER HOMOGENATES FOR ACTIVATION AND BACTERIA FOR DETECTION [J].

AMES, BN ;

DURSTON, WE ;

YAMASAKI, E ;

LEE, FD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1973, 70 (08) :2281-2285

[3] Transcriptional Regulation by p53 [J].

Beckerman, Rachel ;

Prives, Carol .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2010, 2 (08) :a000935

[4] Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma [J].

Beroukhim, Rameen ;

Getz, Gad ;

Nghiemphu, Leia ;

Barretina, Jordi ;

Hsueh, Teli ;

Linhart, David ;

Vivanco, Igor ;

Lee, Jeffrey C. ;

Huang, Julie H. ;

Alexander, Sethu ;

Du, Jinyan ;

Kau, Tweeny ;

Thomas, Roman K. ;

Shah, Kinial ;

Soto, Horacio ;

Perner, Sven ;

Prensner, John ;

Debiasi, Ralph M. ;

Demichelis, Francesca ;

Hatton, Charlie ;

Rubin, Mark A. ;

Garraway, Levi A. ;

Nelson, Stan F. ;

Liau, Linda ;

Mischel, Paul S. ;

Cloughesy, Tim F. ;

Meyerson, Matthew ;

Golub, Todd A. ;

Lander, Eric S. ;

Mellinghoff, Ingo K. ;

Sellers, William R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (50) :20007-20012

[5] SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state [J].

Bilodeau, Steve ;

Kagey, Michael H. ;

Frampton, Garrett M. ;

Rahl, Peter B. ;

Young, Richard A. .

GENES & DEVELOPMENT, 2009, 23 (21) :2484-2489

[6] SELECTIVE G-MUTATION TO T-MUTATION OF P53 GENE IN HEPATOCELLULAR-CARCINOMA FROM SOUTHERN AFRICA [J].

BRESSAC, B ;

KEW, M ;

WANDS, J ;

OZTURK, M .

NATURE, 1991, 350 (6317) :429-431

[7] When mutants gain new powers: news from the mutant p53 field [J].

Brosh, Ran ;

Rotter, Varda .

NATURE REVIEWS CANCER, 2009, 9 (10) :701-713

[8] The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset [J].

Ceol, Craig J. ;

Houvras, Yariv ;

Jane-Valbuena, Judit ;

Bilodeau, Steve ;

Orlando, David A. ;

Battisti, Valentine ;

Fritsch, Lauriane ;

Lin, William M. ;

Hollmann, Travis J. ;

Ferre, Fabrizio ;

Bourque, Caitlin ;

Burke, Christopher J. ;

Turner, Laura ;

Uong, Audrey ;

Johnson, Laura A. ;

Beroukhim, Rameen ;

Mermel, Craig H. ;

Loda, Massimo ;

Ait-Si-Ali, Slimane ;

Garraway, Levi A. ;

Young, Richard A. ;

Zon, Leonard I. .

NATURE, 2011, 471 (7339) :513-+

[9] Regulation of p53 activity through lysine methylation [J].

Chuikov, S ;

Kurash, JK ;

Wilson, JR ;

Xiao, B ;

Justin, N ;

Ivanov, GS ;

McKinney, K ;

Tempst, P ;

Prives, C ;

Gamblin, SJ ;

Barlev, NA ;

Reinberg, D .

NATURE, 2004, 432 (7015) :353-360

[10] Histone H3-K9 methyltransferase ESET is essential for early development [J].

Dodge, JE ;

Kang, YK ;

Beppu, H ;

Lei, H ;

Li, E .

MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (06) :2478-2486

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