Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma.
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.
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hyun Gyu
HG
Lee
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hyemi
H
Kim
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Taekwon
T
Son
Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
Youngtae
Y
Jeong
Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Seung Up
SU
Kim
Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Republic of Korea.
Seung Myung
SM
Dong
Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.|Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Young Nyun
YN
Park
Department of Nuclear Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Republic of Korea.
Jong Doo
JD
Lee
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
Jae Myun
JM
Lee
Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
Jeon Han
JH
Park
D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic
D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006593:Hexokinase
HIF-1α; HK2-CIMP; hexokinase 2; hypoxia response element; HumanMethylation450 BeadChip