title: Enhancer of zeste homolog 2 depletion induces cellular senescence via histone demethylation along the INK4/ARF locus.
abstract: 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.
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: bjbjbj-000@163.com.
authors.forename: Bai
authors.initials: B
authors.lastname: Jie
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: changwl365@foxmail.com.
authors.forename: Chang
authors.initials: C
authors.lastname: Weilong
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: caiming918@21cn.com.
authors.forename: Cai
authors.initials: C
authors.lastname: Ming
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: xu2fei3@163.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Fei
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: liu_xinghua@outlook.com.
authors.forename: Liu
authors.initials: L
authors.lastname: Xinghua
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: lipid@tom.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Junhua
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: Wangguobin1954@126.com.
authors.forename: Wang
authors.initials: W
authors.lastname: Guobin
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: tao_kaixiong@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Kaixiong
authors.affiliation: Department of Gastrointestinal Surgery II, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People's Republic of China. Electronic address: xmshuai@hust.edu.cn.
authors.forename: Shuai
authors.initials: S
authors.lastname: Xiaoming
mesh_terms: D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D025803:Tumor Suppressor Protein p14ARF; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: Cell cycle; Enhancer of zeste homolog 2; Gastric cancer; Histone H3 Lys27 trimethylation; INK4/ARF; Senescence