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Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma

 Hyun Gyu Lee  ;  Hyemi Kim  ;  Taekwon Son  ;  Youngtae Jeong  ;  Seung Up Kim  ;  Seung Myung Dong  ;  Young Nyun Park  ;  Jong Doo Lee  ;  Jae Myun Lee  ;  Jeon Han Park 
 Oncotarget, Vol.7(27) : 41718-41810, 2016 
Journal Title
Issue Date
Biomarkers, Tumor/genetics ; Carcinoma, Hepatocellular/genetics* ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; CpG Islands/genetics* ; DNA Methylation* ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Hexokinase/genetics* ; Hexokinase/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Liver/metabolism ; Liver Neoplasms/genetics* ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Prognosis ; Promoter Regions, Genetic*
HIF-1α ; HK2-CIMP ; hexokinase 2 ; hypoxia response element ; HumanMethylation450 BeadChip
Hexokinase 2 (HK2) is a rate-determining enzyme in aerobic glycolysis, a process upregulated in tumor cells. HK2 expression is controlled by various transcription factors and epigenetic alterations and is heterogeneous in hepatocellular carcinomas (HCCs), though the cause of this heterogeneity is not known. DNA methylation in the HK2 promoter CpG island (HK2-CGI) and its surrounding regions (shore and shelf) has not previously been evaluated, but may provide clues about the regulation of HK2 expression. Here, we compared HK2 promoter methylation in HCCs and adjacent non-cancerous liver tissues using a HumanMethylation450 BeadChip array. We found that, while the HK2-CGI N-shore was hypomethylated, thereby enhancing HK2 expression, the HK2-CGI was itself hypermethylated in some HCCs. This hypermethylation suppressed HK2 expression by inhibiting interactions between HIF-1α and a hypoxia response element (HRE) located at -234/-230. HCCs that were HK2negative and had distinct promoter CGI methylation were denoted as having a HK2-CGI methylation phenotype (HK2-CIMP), which was associated with poor clinical outcome. These findings indicate that HK2-CGI N-shore hypomethylation and HK2-CGI hypermethylation affect HK2 expression by influencing the interaction between HIF 1α and HRE. HK2-CGI hypermethylation induces HK2-CIMP and could represent a prognostic biomarker for HCC
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
김승업(Kim, Seung Up) ORCID logo https://orcid.org/0000-0002-9658-8050
박영년(Park, Young Nyun) ORCID logo https://orcid.org/0000-0003-0357-7967
박전한(Park, Jeon Han) ORCID logo https://orcid.org/0000-0001-9604-3205
이재면(Lee, Jae Myun) ORCID logo https://orcid.org/0000-0002-5273-3113
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