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

He Cui,Pihai Gong,Chengcheng Zhao,Didi Guo,Yuejun Gu,Aifeng Zhang,Huazhang Wu,Yiping Li,Ling Wang,Hong Fan,Shaodan Zhang,Ying Hu,Zhujiang Zhao,Xiaohui Shen

doi:10.1038/s41388-018-0285-1

Abstract

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-β-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.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorised users.Gastric cancer (GC) is one of the most common fatal malignancies worldwide [1]
The results showed that DNMT3Aa and DNMT3A isoform b (DNMT3Ab) were dramatically overexpressed in tumour tissues compared with those in paired adjacent non-tumour tissues (Fig. 1b, c), and upregulation of DNMT3Aa and DNMT3Ab was detected in 37/66 (56.1%) and 41/66 (62.1%) gastric cancer (GC) tissue samples (Supplementary Figure S1a and b)
These findings suggested that DNMT3Ab may contribute to metastasis in patients with GC

Summary

Introduction

Gastric cancer (GC) is one of the most common fatal malignancies worldwide [1]. The prognosis of GC is poor, and the 5-year survival rate of patients with stage IV disease remains nearly 25% [2, 3]. Metastasis in GC is a high potential risk in clinical practice and accounts for a major source of recurrence and mortality [4, 5]. The accumulation of epigenetic alterations is a frequent event during the process of metastasis [6]. A better understanding of the precise epigenetic mechanisms underlying metastasis is critical to provide novel therapeutic strategies for GC patients

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Conclusion