Mechanistic and biological significance of DNA methyltransferase 1 upregulated by growth factors in human hepatocellular carcinoma

Fang,Qin-Liang; Yin,Yi-Rui; Xie,Cheng-Rong; Zhang,Sheng; Zhao,Wen-Xiu; Pan,Chao; Wang,Xiao-Min; Yin,Zhen-Yu

doi:10.3892/ijo.2014.2776

Mechanistic and biological significance of DNA methyltransferase 1 upregulated by growth factors in human hepatocellular carcinoma

Authors:
- Qin-Liang Fang
- Yi-Rui Yin
- Cheng-Rong Xie
- Sheng Zhang
- Wen-Xiu Zhao
- Chao Pan
- Xiao-Min Wang
- Zhen-Yu Yin
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Affiliations: 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, Department of Pathology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, P.R. China
Published online on: November 24, 2014 https://doi.org/10.3892/ijo.2014.2776
Pages: 782-790

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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.

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