title: EZH2 suppresses the nucleotide excision repair in nasopharyngeal carcinoma by silencing XPA gene.
abstract: The enhancer of zeste homolog 2 (EZH2) is involved in a number of fundamental pathological processes of cancer. However, its role in DNA repair pathway is still unclear. Here, we have identified XPA as a novel target gene of EZH2 via a DNA repair pathway PCR array. XPA plays a pivot role in nucleotide excision repair (NER). The expression of XPA was significantly increased by EZH2 specific inhibitor GSK126 or lentiviral shEZH2 in nasopharyngeal carcinoma (NPC) CNE and 8F cell lines. Chromatin immunoprecipitation assay demonstrated that EZH2 catalyzes H3K27 trimethylation at the XPA promoters. Furthermore, we validated the negative correlation of EZH2 and XPA in a NPC tissue microarray by immunohistochemistry staining. We also found that high expression of EZH2 was positively correlated with advanced T, N, and AJCC stage of NPC; and low expression of XPA was positively correlated with advanced T and N stage. In NPC cell lines, increased XPA expression by EZH2 inhibition resulted in a more rapid removal of UVC induced 6-4PP- and CPD-DNA adducts, as well as enhanced efficiency of DNA repair after UVC irradiation as detected by the Comet assay and immunofluorescence staining of γH2Ax. Consistently, increased cell clonogenic survival, decreased apoptosis, and necrosis after UVC irradiation, and increased resistance to DNA damaging agent cisplatin was also observed in EZH2 inhibited cells. These results illustrate that EZH2 may promote carcinogenesis and cancer development of NPC by transcriptional repression of XPA gene and inactivation of NER pathway. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Traditional Chinese Medicine and Western Medicine, School of Medicine, Yangzhou University, Yangzhou, China.
authors.forename: Xuanyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Niu
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Xiaoshen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Ou
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Chaosu
authors.initials: C
authors.lastname: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair; D015536:Down-Regulation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D042421:Histone Code; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009305:Nasopharynx / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D051760:Xeroderma Pigmentosum Group A Protein / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D000071221:Enhancer of Zeste Homolog 2 Protein; D002945:Cisplatin
keywords: EZH2; XPA; nasopharyngeal carcinoma; nucleotide excision repair