Enhancer of zeste homolog 2 depletion induces cellular senescence via histone demethylation along the INK4/ARF locus

被引:15
作者
Bai, Jie [1 ]
Chang, Weilong [1 ]
Cai, Ming [1 ]
Xu, Fei [1 ]
Liu, Xinghua [1 ]
Chen, Junhua [1 ]
Wang, Guobin [1 ]
Tao, Kaixiong [1 ]
Shuai, Xiaoming [1 ]
机构
[1] Huazhong Univ Sci & Technol, Union Hosp, Dept Gastrointestinal Surg 2, Tongji Med Coll, Wuhan 430022, Hubei Province, Peoples R China
关键词
Enhancer of zeste homolog 2; Gastric cancer; Senescence; Cell cycle; INK4/ARF; Histone H3 Lys27 trimethylation; GASTRIC-CANCER; INK4A/ARF LOCUS; CELLS; EZH2; P53; TUMORIGENESIS; P16(INK4A); PROLIFERATION; FIBROBLASTS; METHYLATION;
D O I
10.1016/j.biocel.2015.05.011
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Polycomb group proteins are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. As a member of PcG proteins, enhancer of zeste homolog 2 (EZH2) targets cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. In previous work, we reported that EZH2 depletion functionally induced cellular senescence in human gastric cancer cells with mutant p53. However, whether EZH2 expression contributes to the change of key cell cycle regulators and the mechanism involved are still unclear. To address this issue, we investigated the effects of EZH2 depletion on alteration of histone methylation pattern. In gastric cancer cells, INK4/ARF locus was activated to certain extent in consequence of a decrease of H3K27me3 along it caused by EZH2 silence, which contributed substantially to an increase in the expression of p15(INK4b), p14(ARF) and p16(INK4a) and resulted in cellular senescence ultimately. Furthermore, MKN28 cells, which did not express p16(INK4a) and p21(cip), could be induced to senescence via p15(INK4b) activation and suppression of p15(INK4b) reversed senescence progression induced by EZH2 downregulated. These data unravel a crucial role of EZH2 in the regulation of INK4/ARF expression and senescence procedure in gastric cancer cells, and show that the cellular senescence could just depend on the activation of p15(INK4b)/Rb pathway, suggesting the cell-type and species specificity involved in the mechanisms of senescence inducement. Crown Copyright (C) 2015 Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:104 / 112
页数:9
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