Decreased expression of GRIM-19 by DNA hypermethylation promotes aerobic glycolysis and cell proliferation in head and neck squamous cell carcinoma
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Xiao-Yun Zhang1,*, Minle Li2,*, Kai Sun1,*, Xiao-Jie Chen1, Jian Meng2, Lifang Wu2, Ping Zhang2, Xuemei Tong2, Wei-Wen Jiang1
1Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
2Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
*These authors contributed equally to this work
Wei-Wen Jiang, e-mail: email@example.com
Xuemei Tong, e-mail: firstname.lastname@example.org
Keywords: GRIM-19, methylation, HNSCC, proliferation, metabolism
Received: August 04, 2014 Accepted: November 02, 2014 Published: December 23, 2014
To identify novel tumor suppressor genes that are down-regulated by promoter hypermethylation in head and neck squamous cell carcinoma (HNSCC), genome-wide methylation profiling was performed using a methylated DNA immunoprecipitation (MeDIP) array in HNSCC and normal mucosa tissue samples. Promoter hypermethylation of the candidate gene, gene associated with retinoid-interferon induced mortality-19 (GRIM-19), was confirmed in HNSCC cell lines. Multivariate regression analysis determined that GRIM-19 hypermethylation was an independent significant factor for HNSCC diagnosis (OR:125.562; P < 0.001). HNSCC patients with lower ratio of GRIM-19/ACTB hypermethylation had increased overall and disease free survival. Furthermore, the optimal cutoff provided 90% sensitivity and 77% specificity of GRIM-19 hypermethylation as a diagnostic marker for HNSCC. Ectopic expression of GRIM-19 in HNSCC cells led to increased oxygen consumption, reduced glycolysis and decreased cell proliferation. HNSCC cells ectopically expressing GRIM-19 displayed increased p53 activity as well as decreased Stat3 and HIF-1α activities. Moreover, GRIM-19 knockdown not only resulted in decreased oxygen consumption and increased aerobic glycolysis but also promoted cell proliferation and tumorigenic capacity in HNSCC cells. Our data indicate that decreased GRIM-19 expression due to promoter hypermethylation may be important in head and neck carcinogenesis by promoting cell proliferation and regulating metabolic activity.
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