title: EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer.
abstract: Histone methylations play important roles in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2) is a key component of the polycomb repressor complex 2, which is responsible for histone H3K27 methylation. EZH2 is overexpressed in lung cancer and epigenetically silences tumor suppressor genes. Here, we showed that EZH2 was up-regulated in lung cancer and had a positive correlation with pathologic stage, nodal involvement in lung cancer patients. Moreover, overexpression of EZH2 was correlated with reduced tissue inhibitor of metalloproteinase-3 (TIMP-3) expression, which was shown to be negatively associated with tumor metastasis. Of note, overall survival time of patients with high EZH2/low TIMP-3 expression was significantly shorter than that of patients with low EZH2/high TIMP-3 (P = 0.031). RNA interfering and pharmacologic inhibition of EZH2 reduced histone H3 lysine 27 tri-methylation level and increased TIMP-3 expression level. Knockdown of EZH2 by siRNA significantly reduced A549 cancer cell migration. In contrast, reduction of TIMP-3 in A549 cells partially rescued EZH2 deficiency-induced loss of cell migration capacity. Taken together, our findings indicate that EZH2 accelerates cancer cell migration, in part, via the repression of TIMP-3 expression, suggesting a potential mechanism by which EZH2 promotes lung cancer progression and metastasis.
authors.affiliation: First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, 210029, Jiangsu, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Xu
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Hou
authors.forename: Ping
authors.initials: P
authors.lastname: Zhan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Cunjie
authors.initials: C
authors.lastname: Chang
authors.forename: Jue
authors.initials: J
authors.lastname: Zou
authors.forename: Huidi
authors.initials: H
authors.lastname: Hu
authors.forename: Yuanqin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.forename: Like
authors.initials: L
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2