DNA methyltransferase 3A isoform b contributes to repressing Ecadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer

被引：59

作者：

Cui, He ^{[1
,2
,3
]}

Hu, Ying ^{[1
]}

Guo, Didi ^{[1
]}

Zhang, Aifeng ^{[4
]}

Gu, Yuejun ^{[1
]}

Zhang, Shaodan ^{[1
]}

Zhao, Chengcheng ^{[1
]}

Gong, Pihai ^{[1
]}

Shen, Xiaohui ^{[1
]}

Li, Yiping ^{[4
]}

Wu, Huazhang ^{[1
]}

Wang, Ling ^{[1
]}

Zhao, Zhujiang ^{[1
]}

Fan, Hong ^{[1
]}

机构：

[1] Southeast Univ, Dept Med Genet & Dev Biol, Key Lab Dev Genes & Human Dis, Med Sch,Minist Educ, Nanjing 210009, Jiangsu, Peoples R China

[2] Jiangsu Prov Hosp, Nanjing 210029, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Affiliated Hosp 1, Nanjing 210029, Jiangsu, Peoples R China

[4] Southeast Univ, Sch Med, Dept Pathol, Nanjing 210009, Jiangsu, Peoples R China

来源：

ONCOGENE | 2018年 / 37卷 / 32期

基金：

中国国家自然科学基金;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; CLINICAL-SIGNIFICANCE; EXPRESSION; DNMT3A; CELLS; STEM; PROTEINS; SNAIL; GENE;

D O I：

10.1038/s41388-018-0285-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

DNA methyltransferase 3A (DNMT3A) has been recognised as a key element of epigenetic regulation in normal development, and the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours remain unknown, although abnormal expression has gained widespread attention in these cancers. Here, we show that DNMT3A isoform b (DNMT3Ab), a member of the DNMT3A isoform family, is critical for directing epithelial-mesenchymal transition (EMT)-associated metastasis in gastric cancer (GC). DNMT3Ab is positively linked to tumour-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis in GC patients. Overexpression of DNMT3Ab promotes GC cell migration and invasion as well as EMT through repression of E-cadherin. Meanwhile, DNMT3Ab promotes lung metastasis of GC in vivo. Mechanistic studies indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF-beta-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. Further, gene expression profiling analysis indicates that multiple metastasis-associated genes and oncogenic signalling pathways are regulated in response to DNMT3Ab overexpression. These results identify DNMT3Ab as a crucial regulator of metastasis-related genes in GC. Targeting the DNMT3Ab/Snail/E-cadherin axis may provide a promising therapeutic strategy in the treatment of metastatic GC with high DNMT3Ab expression.

引用

页码：4358 / 4371

页数：14