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.

中文翻译：

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DNA甲基转移酶3A亚型b通过在胃癌EMT相关转移中的DNA甲基化和H3K27 / H3K9甲基化协同作用来抑制E-钙粘着蛋白。

DNA甲基转移酶3A（DNMT3A）已被认为是正常发育中表观遗传调控的关键因素，DNMT3A的异常调控与多种类型的癌症有关，尤其是血液系统恶性肿瘤。然而，尽管异常表达已在这些癌症中引起广泛关注，但其在实体瘤中的临床意义和详细的功能作用仍然未知。在这里，我们显示DNMT3A同工型家族DNMT3A同工型b（DNMT3Ab）对于指导胃癌（GC）上皮-间质转化（EMT）相关的转移至关重要。DNMT3Ab与GC患者的肿瘤淋巴结转移（TNM）分期，淋巴结转移和预后不良呈正相关。DNMT3Ab的过表达通过抑制E-cadherin促进GC细胞迁移和侵袭以及EMT。同时，DNMT3Ab在体内促进了GC的肺转移。机理研究表明，DNMT3Ab通过DNA超甲基化和H3K9me2和H3K27me3的组蛋白修饰介导E-钙粘蛋白基因的表观遗传失活。DNMT3Ab的消耗可通过减少E-钙粘蛋白启动子上的DNA甲基化，H3K9me2和H3K27me3水平来有效恢复E-钙粘蛋白的表达并逆转TGF-β诱导的EMT。重要的是，DNMT3Ab与H3K9me2和H3K27me3协同作用，以Snail依赖性方式促进E-钙粘着蛋白的转录调控。此外，基因表达谱分析表明响应于DNMT3Ab过表达，多个转移相关基因和致癌信号通路受到调节。这些结果确定了DNMT3Ab是GC中转移相关基因的重要调节剂。