Mechanistic and biological significance of DNA methyltransferase 1 upregulated by growth factors in human hepatocellular carcinoma
Mechanistic and biological significance of DNA methyltransferase 1 upregulated by growth factors in human hepatocellular carcinoma
复制标题
生长因子上调人肝细胞癌DNA甲基转移酶1的机制和生物学意义
DOI：
10.3892/ijo.2014.2776
复制
发表时间：
2015-02-01
影响因子：
5.2
通讯作者：
Yin, Zhen-Yu
中科院分区：
文献类型：
--
作者：
Fang, Qin-Liang;Yin, Yi-Rui;Yin, Zhen-Yu
生长因子信号的失调在控制肝细胞癌（HCC）的恶性表型和进展中起着关键作用。然而，生长因子对某些肿瘤抑制基因（TSGs）转录调控的确切致癌机制尚不清楚。在本研究中，我们报道了一种新的胰岛素样生长因子1 （IGF1）途径，该途径通过AKT/ β -转导重复蛋白（β - TrCP）介导的泛素-蛋白酶体途径，通过DNA甲基化酶1 （DNMT1）的上调，介导肝癌中DNA甲基化和TSG（如dcl1和CHD5）的沉默。靶基因CpG岛DNA甲基化分析显示，DNMT1和DNMT3B在tsg启动子上高度共定位，与CpG高甲基化增强相关。我们的研究结果指出了一种新的表观遗传机制，即生长因子介导的TSG转录抑制涉及DNA甲基化。
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/beta-transducin repeat-containing protein (beta TrCP)-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.