Abstract
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.
Highlights
Hexokinase 2 (HK2) is a rate-determining enzyme in aerobic glycolysis
Because altered methylation in the HK2 promoter CpG island (HK2-CpG island (CGI)) and its N-shore should correlate with the regulation of HK2 expression, we investigated the relationship of methylation status of HK2 promoter with HK2 protein expression (Figure 1B upper panel)
We investigated the influence of HK2-CGI methylation on HK2 expression under conditions where the interaction between Hypoxia-inducible factor-1α (HIF-1α) and newly defined -234/230 hypoxia response element (HRE) was blocked
Summary
Hexokinase 2 (HK2) is a rate-determining enzyme in aerobic glycolysis. HK2 is rarely expressed in normal tissues, except skeletal and cardiac muscle and adipose tissues [1]; it is frequently upregulated in tumor cells, leading to a phenomenon known as the Warburg Effect.In spite of frequent HK2 expression in various cancers [2], hepatocellular carcinomas (HCCs) exhibit heterogeneous expression of HK2 [3,4,5], which contributes to heterogeneous 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) uptake in positron emission tomography (PET) scan [6, 7] and reduces the clinical usefulness of 18F-FDG PET in HCCs [8, 9]. HK2 is rarely expressed in normal tissues, except skeletal and cardiac muscle and adipose tissues [1]; it is frequently upregulated in tumor cells, leading to a phenomenon known as the Warburg Effect. Defining the mechanisms underlying HK2 expression could give a clue about the heterogeneous expression of HK2 in HCCs. Various transcription factors and microRNAs are involved in the regulation of HK2 expression during cancer initiation and progression [11, 12]. HIF-1α was implicated in the indirect regulation of HK2 expression via the suppression of miR199a-5p [14]. Despite these findings, little is known about how HIF-1α directly regulates HK2 expression [15, 16]
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