title: MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer.
abstract: Hypoxia-inducible factor 2α (HIF2α) plays critical roles in cancer progression. Although the mechanisms of HIF2α translation and degradation have been well studied, the mechanism for HIF2α regulation at transcriptional level is still not fully understood. Here, we present evidence that DNA methylation in promoter contributes to transcription of EPAS1 coding HIF2α. Methylated CpG binding protein 3 (MBD3) contributes to the intricate regulatory mechanism. We showed that MBD3 bound to the EPAS1 promoter in breast cancer cells and amplified EPAS1 transcription through demethylating CpG located around transcriptional start site in MDA-MB-468 cells. This enabled MDA-MB-468 cells to activate HIF2α-mediated angiogenesis. However, in 7860 cells, the demethylation function of MBD3 on EPAS1 was not observed because of the poor methylated-CpG promoter. Nevertheless, depletion of MBD3 induced by shRNA decreased EPAS1 transcription and therefore decreased HIF2α-mediated cellular response in both MDA-MB-468 and 7860 cancer cells. These results indicated that the endogenous MBD3 was involved in regulating the transcription and therefore the transcriptional activities of HIF2α, suggesting that MBD3 may be a potential therapeutic target of tumor.
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.|Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Duan
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Shixun
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Physiology, University of Jiangsu, Zhenjiang, Jiangsu, 212013, China.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. lgu@njmu.edu.cn.|Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. lgu@njmu.edu.cn.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, 101 Longmindadao Road, Nanjing, Jiangsu, 211166, China. lgu@njmu.edu.cn.
authors.forename: Luo
authors.initials: L
authors.lastname: Gu
mesh_terms: D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024363:Transcription Initiation Site; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C115369:MBD3 protein, human
keywords: Cancer; EPAS1; MBD3; Methylation