title: Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway.
abstract: Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the autophagy regulation machinery has been widely studied, the key epigenetic control of autophagy process still remains unknown. Here we report that the methyltransferase EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) epigenetically represses several negative regulators of the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) pathway, such as TSC2, RHOA, DEPTOR, FKBP11, RGS16 and GPI. EZH2 was recruited to these genes promoters via MTA2 (metastasis associated 1 family, member 2), a component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA2 was identified as a new chromatin binding protein whose association with chromatin facilitated the subsequent recruitment of EZH2 to silenced targeted genes, especially TSC2. Downregulation of TSC2 (tuberous sclerosis 2) by EZH2 elicited MTOR activation, which in turn modulated subsequent MTOR pathway-related events, including inhibition of autophagy. In human colorectal carcinoma (CRC) tissues, the expression of MTA2 and EZH2 correlated negatively with expression of TSC2, which reveals a novel link among epigenetic regulation, the MTOR pathway, autophagy induction, and tumorigenesis.
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Fu-Zheng
authors.initials: FZ
authors.lastname: Wei
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Cao
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: b State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center ; Guangzhou , China.
authors.forename: Mu-Yan
authors.initials: MY
authors.lastname: Cai
authors.affiliation: c Department of Biomedical Informatics ; School of Basic Medical Sciences; Peking University Health Science Center ; Beijing , China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: d Division of Epigenomics; National Cancer Center Research Institute ; Tokyo , Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hattori
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Donglai
authors.initials: D
authors.lastname: Wang
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Boyan
authors.initials: B
authors.lastname: Song
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Cao
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Changchun
authors.initials: C
authors.lastname: Shen
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: b State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center ; Guangzhou , China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: e Department of Radiation Medicine; School of Basic Medical Sciences ; Peking University ; Beijing , People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: d Division of Epigenomics; National Cancer Center Research Institute ; Tokyo , Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: a Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); State Key Laboratory of Natural and Biomimetic Drugs; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology; Peking University Health Science Center ; Beijing , China.|f Peking University-Tsinghua University Center for Life Sciences ; Beijing , China.|g School of Medicine; Shenzhen University ; Shenzhen , China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
mesh_terms: D001343:Autophagy / Q000235:genetics*; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases
keywords: EZH2; MTA2; MTOR pathway; autophagy; histone modification