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Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway
Authors:Fu-Zheng Wei  Ziyang Cao  Xi Wang  Hui Wang  Mu-Yan Cai  Tingting Li  Naoko Hattori  Donglai Wang  Yipeng Du  Boyan Song  Lin-Lin Cao  Changchun Shen  Lina Wang  Haiying Wang  Yang Yang  Dan Xie  Fan Wang  Toshikazu Ushijima  Ying Zhao  Wei-Guo Zhu
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.
Keywords:autophagy   EZH2   histone modification   MTA2   MTOR pathway
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