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.

EZH2 inhibition promotes methyl jasmonate‑induced apoptosis of human colorectal cancer through the Wnt/β‑catenin pathway

“…T24 cells were seeded in a 96-well plate at a density of 2x10 6 cells per well and cultured with DMSO (5 mM) or methyl jasmonate (0.75, 1.5 and 2.0 mM) for 48 h. Apoptotic rates were assessed using flow cytometry following fluorescein isothiocyanate-conjugated annexin V and propidium iodide staining (BD Pharmingen™ FITC Annexin V; cat. no.…”

“…Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is a novel polycomb-group gene identified in Drosophila melanogaster; in 2000, its chromosomal locus was determined to be 7q35 in humans (6). Previous studies revealed that the EZH2 gene participated in cellular growth regulation (6,7).…”

“…Previous studies revealed that the EZH2 gene participated in cellular growth regulation (6,7). The mechanism underlying the function of EZH2 function was the inhibition of the Wnt signaling pathway in chromatin and the promotion of cell proliferation (7,8).…”

Synergistic effects of phenylhexyl isothiocyanate and LY294002 on the PI3K/Akt signaling pathway in HL-60 cells

“…Resistance to histone deacetylase inhibitors in non-small cell lung cancer is mediated in part through the activation of nuclear factor-κβ through the phosphatidylinositol 3-kinase/Akt-dependent pathway (41). A number of studies (42)(43)(44) have indicated that the dynamic changes of histone modification may regulate mTOR signaling pathway protein kinase activity. However, the underlying molecular mechanism remains unknown.…”

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

“…EHMT2/G9a (euchromatic histone lysine methyltransferase 2) [14] and EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) [15] have both been implicated in autophagy repression under serum starvation by increasing H3K9me2 and H3K27me3 histone mark levels, respectively, of certain autophagy-associated genes. Furthermore, autophagy induction has been demonstrated to affect total H3R17me2, H4K16ac, and H2BK120ub levels through CARM1 (coactivator associated arginine methyltransferase 1) [16], KAT8/hMOF (lysine acetyltransferase 8) [17], and the deubiquitinase USP44 (ubiquitin specific peptidase 44) [18], respectively.…”