Abstract C35: Epigenetic repression of hexokinase 2 is responsible for the heterogeneity of 18F-FDG uptake in hepatocellular carcinoma

Abstract

Abstract The clinical usefulness of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET), based on aerobic glycolysis, has been recently challenged in hepatocellular carcinoma (HCC) due to the heterogeneity of 18F-FDG uptake. Although inconsistent 18F-FDG uptake in HCCs is explained by the heterogeneous expression of hexokinase 2 (HK2), the underlying molecular mechanism remains elusive. Here, we examined the methylation status of the HK2 promoter and its influence on hypoxia-inducible factor-1α (HIF-1α) binding. We first confirmed inconsistent 18F-FDG uptake and correlative HK2 expression. Utilizing the HumanMethylation450 array, we discovered hypermethylation of the HK2 promoter CpG island (CGI) region in HK2negative HCCs. Studies using HK2 promoter luciferase constructs showed that a newly defined hypoxia responsive element (HRE) regulates HK2 expression. We also found that differential glucose uptake is caused by the differential HK2 expression due to differential methylation of the HK2 promoter CGI region in HCC cell lines. Finally, treatment with 5-Aza-2-deoxycytidine and hypoxic stimuli significantly increased HK2 expression due to increased HIF-1α binding to the HRE, resulting in increased glucose uptake in HK2negative SNU449 cells. Conclusion: These data indicate that methylation changes in the HK2 promoter CGI region in HCCs influence HK2 expression by regulating HIF-1α binding to the HRE in the CGI region. Hypermethylation of the HK2 promoter CGI region in HK2negative tissues inhibits the binding of HIF-1α to the HK2 promoter, resulting in the suppression of HK2 expression, which contributes to the heterogeneity of 18F-FDG uptake. Citation Format: Kim Hyemi, Lee Hyun Gyu, Lee Jae Myun, Park Jeon Han. Epigenetic repression of hexokinase 2 is responsible for the heterogeneity of 18F-FDG uptake in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C35.