title: FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated tumor prevalent in southern China and southeast Asia, with the 3p14-p12 locus reported as a critical tumor suppressor gene (TSG) region during its pathogenesis. We identified a novel 3p14.2 TSG, FEZF2 (FEZ family zinc finger 2), for NPC. FEZF2 is readily expressed in normal tissues including upper respiratory epithelium, testis, brain and ovary tissues, as well as in immortalized nasopharyngeal epithelial cell line NP69, but it is completely silenced in NPC cell lines due to CpG methylation of its promoter, although no homozygous deletion of FEZF2 was detected. 5-Aza-2'-deoxycytidine treatment restored FEZF2 expression in NPC cell lines along with its promoter demethylation. FEZF2 was frequently downregulated in NPC tumors, with promoter methylation detected in 75.5% of tumors, but only in 7.1% of normal nasopharyngeal tissues. Restored FEZF2 expression suppressed NPC cell clonogenicity through inducing G2/M cell cycle arrest and apoptosis and also inhibited NPC cell migration and stemness. FEZF2 acted as a histone deacetylase-associated repressor downregulating multiple oncogenes including EZH2 and MDM2, through direct binding to their promoters. Concomitantly, overexpression of EZH2 was frequently detected in NPC tumors. Thus, we have identified FEZF2 as a novel 3p14.2 TSG frequently inactivated by promoter methylation in NPC, which functions as a repressor downregulating multiple oncogene expression.
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong.
authors.forename: Xing-Sheng
authors.initials: XS
authors.lastname: Shu
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Mingfang
authors.initials: M
authors.lastname: Ji
authors.forename: Yingduan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.forename: Yichao
authors.initials: Y
authors.lastname: Fan
authors.forename: Lan
authors.initials: L
authors.lastname: Zhong
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D002277:Carcinoma; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D004847:Epithelial Cells; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009305:Nasopharynx / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C557090:FEZF2 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2