title: Cytochrome b5 reductase 2 is a novel candidate tumor suppressor gene frequently inactivated by promoter hypermethylation in human nasopharyngeal carcinoma.
abstract: Cytochrome b5 reductase 2 (CYB5R2), a member of the flavoprotein pyridine nucleotide cytochrome reductase family, is associated with a number of physiological reactions. However, its role in cancer, especially nasopharyngeal carcinoma (NPC), has not been addressed. Here, we investigate the transcript levels and promoter methylation status of CYB5R2 in NPC derived cell lines and tumor biopsies and experimentally address its role as a tumor suppressor gene. We find that CYB5R2 transcript levels are decreased in NPC cell lines and tumor biopsies. Promoter hypermethylation of CYB5R2 was detected in all six tested NPC cell lines and in 84% of primary NPC tumor biopsies but not in normal nasopharyngeal epithelium. Clinically, CYB5R2 methylation was associated with lymph node metastasis in NPC patients (P < 0.05). The endogenous expression of CYB5R2 could be restored in vitro by the methyltransferase inhibitor 5-aza-2'-deoxycytidine in NPC cell lines. Ectopic expression of CYB5R2 had an inhibitory effect on proliferation, clonogenicity and migration of NPC cells. Moreover, in vivo tests in nude mice indicated that ectopic expression of CYB5R2 reduces the tumorigenicity of CYB5R2-negative NPC cells. Collectively, these findings suggest that CYB5R2 may be a functional tumor suppressor gene, frequently inactivated by hypermethylation of its promoter in NPC. We report here the first instance of epigenetic downregulation in NPC tumor biopsies of a key enzyme, CYB5R2, which is responsible for the detoxification of environmental carcinogens. We propose the possibility of utilizing CYB5R2 promoter methylation as a diagnostic biomarker of NPC in the future.
authors: Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, 6# Shuangyong Road, Nanning, 530021, China.
authors: Xue
authors: X
authors: Xiao
authors: Weilin
authors: W
authors: Zhao
authors: Fangyun
authors: F
authors: Tian
authors: Xiaoying
authors: X
authors: Zhou
authors: Jinyan
authors: J
authors: Zhang
authors: Tingting
authors: T
authors: Huang
authors: Bo
authors: B
authors: Hou
authors: Chunping
authors: C
authors: Du
authors: Shumin
authors: S
authors: Wang
authors: Yingxi
authors: Y
authors: Mo
authors: Nana
authors: N
authors: Yu
authors: Shiping
authors: S
authors: Zhou
authors: Jinping
authors: J
authors: You
authors: Zhe
authors: Z
authors: Zhang
authors: Guangwu
authors: G
authors: Huang
authors: Xianjie
authors: X
authors: Zeng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042966:Cytochrome-B(5) Reductase / Q000235:genetics*; D019175:DNA Methylation; D000077209:Decitabine; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D014408:Biomarkers, Tumor; D000077209:Decitabine; D042966:Cytochrome-B(5) Reductase; D001374:Azacitidine