title: DNMT1 and EZH2 mediated methylation silences the microRNA-200b/a/429 gene and promotes tumor progression.
abstract: Aberrant expression of the microRNA-200 (miR-200) family has been linked to the occurrence and development of various types of malignant tumors, including hepatocellular carcinoma (HCC), colon cancer and breast cancer. However, little is known about the precise mechanism by which miR-200 expression is downregulated. The intricate relationship between DNA methylation and histone modifications has become a subject of increasing interest. The expression of miR-200 family members is modified by similar or complementary epigenetic mechanisms in MGC-803 and BGC-823 gastric cancer cells and U87 MG glioma cells. Chromatin immunoprecipitation assays revealed that DNA methyltransferase 1 (DNMT1) bound to miR-200b/a/429 promoter regions, indicating an interaction between DNMT1 and the miR-200b/a/429 promoter. Furthermore, Co-Immunoprecipitation (Co-IP) detection showed that DNMT1, together with the PcG protein Enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase, contributed to the transcriptional repression of microRNA-200 family members. Knockdown of EZH2 not only impacted H3K27 trimethylation but also reduced DNMT1 presence on the miR-200b/a/429 promoter. EZH2 appeared to be essential for DNMT1 recruitment to the promoter region. Silencing EZH2 and DNMT1 using drugs or RNA interference dramatically reduced the levels of miR-200b/a/429 expression. Collectively, these results indicated that EZH2 and DNMT1-mediated epigenetic silencing contributed to the progression of gastric cancer and glioblastoma, and therefore represents a novel therapeutic target for malignant tumors.
authors.affiliation: Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Ning
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, 154 An-Shan Road, Heping District, Tianjin 300052, China; The 3rd Department of Breast Cancer Prevention, Treatment and Research Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, 154 An-Shan Road, Heping District, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China.
authors.forename: Anling
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, 154 An-Shan Road, Heping District, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, 154 An-Shan Road, Heping District, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China; Chinese Glioma Cooperative Group (CGCG), 6 Tiantanxi Li, Beijing, China. Electronic address: kang97061@gmail.com.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China. Electronic address: zhangqy@tijmu.edu.cn.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019175:DNA Methylation; D000077209:Decitabine; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000628:therapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013274:Stomach Neoplasms / Q000628:therapy; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C048460:3-deazaneplanocin; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000241:Adenosine; D001374:Azacitidine
keywords: DNA methylation; DNMT; EZH2; Histone modifications; miR-200