title: Mechanistic and biological significance of DNA methyltransferase 1 upregulated by growth factors in human hepatocellular carcinoma.
abstract: Dysregulation of growth factor signaling plays a pivotal role in controlling the malignancy phenotype and progression of hepatocellular carcinoma (HCC). However, the precise oncogenic mechanisms underlying transcription regulation of certain tumor suppressor genes (TSGs) by growth factors are poorly understood. In the present study, we report a novel insulin-like growth factor 1 (IGF1) pathway that mediates de novo DNA methylation and TSG (such as DLC1 and CHD5) silencing by upregulation of the DNA methyltransferase 1 (DNMT1) via an AKT/β-transducin repeat-containing protein (βTrCP)-mediated ubiquitin-proteasome pathway in HCC. Analysis of DNA methylation in CpG islands of target genes revealed high co-localization of DNMT1 and DNMT3B on the promoters of TSGs associated with enhanced CpG hypermethylation. Our results point to a novel epigenetic mechanism for growth factor-mediated repression of TSG transcription that involves DNA methylation.
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Qin-Liang
authors.initials: QL
authors.lastname: Fang
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Yi-Rui
authors.initials: YR
authors.lastname: Yin
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Xie
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Wen-Xiu
authors.initials: WX
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, P.R. China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Yin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018390:Gene Targeting; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse