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Autophagy. 2015;11(12):2309-22. doi: 10.1080/15548627.2015.1117734.

Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway.

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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.
b State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center ; Guangzhou , China.
c Department of Biomedical Informatics ; School of Basic Medical Sciences; Peking University Health Science Center ; Beijing , China.
d Division of Epigenomics; National Cancer Center Research Institute ; Tokyo , Japan.
e Department of Radiation Medicine; School of Basic Medical Sciences ; Peking University ; Beijing , People's Republic of China.
f Peking University-Tsinghua University Center for Life Sciences ; Beijing , China.
g School of Medicine; Shenzhen University ; Shenzhen , China.


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.


EZH2; MTA2; MTOR pathway; autophagy; histone modification

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