Decreased expression of GRIM-19 by DNA hypermethylation promotes aerobic glycolysis and cell proliferation in head and neck squamous cell carcinoma.

Xiao-Yun Zhang,Lifang Wu,Ping Zhang,Jian Meng,Minle Li,Wei-Wen Jiang,Xiao-Jie Chen,Kai Sun,Xuemei Tong

doi:10.18632/oncotarget.2684

Abstract

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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancer, accounting for over 650,000 new cases and 350,000 cancer deaths every year worldwide [1,2,3] and HNSCC incidence increases with age
We demonstrated a genome-wide methylation profile and screened for differentially methylated CpG islands (CGIs) and candidate genes in tissue samples from HNSCC and normal oral mucosa
We identified and confirmed a novel promoter hypermethylation in gene associated with retinoid-interferon induced mortality-19 (GRIM-19) in patients with HNSCC

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancer, accounting for over 650,000 new cases and 350,000 cancer deaths every year worldwide [1,2,3] and HNSCC incidence increases with age. Many efforts have been attempted to identify molecular events that occur during HNSCC development, including the inactivation of TP53, Notch mutations [4, 5], and altered metabolites [6]. Further elucidation of the molecular mechanisms in head and neck carcinogenesis are expected to accelerate the development of efficacious anticancer agents and the identification of diagnostic or therapeutic biomarkers. DNA methylation is associated with a number of key processes, including embryonic development, X chromosome inactivation, and genomic imprinting. The role of DNA methylation www.impactjournals.com/oncotarget in HNSCC initiation and progression remains largely unknown [8]

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