title: Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fei
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Shang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chuai
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Kong
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Fu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Ying
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Zhui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xing
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Chris
authors.initials: C
authors.lastname: Lu
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Xiao
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.affiliation: Novartis Institutes for BioMedical Research, Shanghai 201203, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Shou
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D056915:DNA Copy Number Variations; D016158:Genes, p53; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008819:Mice, Nude; D011496:Protein Methyltransferases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human