title: Hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells.
abstract: Hypoxia-inducible factor 1 (HIF-1) emerges as a crucial player in tumor progression. However, its role in hepatocellular carcinoma (HCC), especially its relation with global DNA methylation patterns in HCC under hypoxic tumor microenvironment is not completely understood. Methionine adenosyltransferase 2A (MAT2A) maintains the homeostasis of S-adenosylmethionine (SAM), a critical marker of genomic methylation status. In this study, we investigated the link between HIF-1α and MAT2A as a mechanism responsible for the change in genomic DNA methylation patterns in liver cancer under hypoxia conditions. Our results showed that hypoxia induces genomic DNA demethylation in CpG islands by reducing the steady-state SAM level both in vitro and in vivo. In addition, HIF-1α and MAT2A expression is correlated with tumor size and TNM stage of liver cancer tissues. We further showed that hypoxia-induced MAT2A expression is HIF-1α dependent and requires the recruitment of p300 and HDAC1. We also identified an authentic consensus HIF-1α binding site in MAT2A promoter by site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Taken together, we show for the first time that hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells. These findings provide new insights into our understanding of the molecular link between genomic DNA methylation and tumor hypoxia in HCC.
authors: Department of General Surgery, Zhongnan Hospital, Wuhan, China.
authors: Quanyan
authors: Q
authors: Liu
authors: Li
authors: L
authors: Liu
authors: Yuhong
authors: Y
authors: Zhao
authors: Jin
authors: J
authors: Zhang
authors: Dongfeng
authors: D
authors: Wang
authors: Jiwei
authors: J
authors: Chen
authors: Yueming
authors: Y
authors: He
authors: Jianguo
authors: J
authors: Wu
authors: Zhonglin
authors: Z
authors: Zhang
authors: Zhisu
authors: Z
authors: Liu
mesh_terms: D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008716:Methionine Adenosyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D059016:Tumor Microenvironment; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012436:S-Adenosylmethionine; D004247:DNA; D012435:S-Adenosylhomocysteine; D050880:p300-CBP Transcription Factors; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1