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.
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.
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DNA 甲基转移酶 3A 亚型 b 通过 DNA 甲基化和 H3K27/H3K9 甲基化在胃癌 EMT 相关转移中的协同作用抑制 Ecadherin
DOI：
10.1038/s41388-018-0285-1
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发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
Fan H
中科院分区：
文献类型：
--
作者：
Cui H;Hu Y;Guo D;Zhang A;Gu Y;Zhang S;Zhao C;Gong P;Shen X;Li Y;Wu H;Wang L;Zhao Z;Fan H
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，特别是血液系统恶性肿瘤有关。然而，其在实体肿瘤中的临床意义和详细的功能作用尚不清楚，尽管异常表达在这些癌症中得到了广泛的关注。在这里，我们发现DNMT3A亚型b （DNMT3Ab）是DNMT3A亚型家族的一员，在胃癌（GC）中对指导上皮-间质转化（EMT）相关转移至关重要。DNMT3Ab与胃癌患者的肿瘤淋巴结转移（TNM）分期、淋巴结转移和不良预后呈正相关。过表达DNMT3Ab通过抑制E-cadherin促进GC细胞的迁移和侵袭以及EMT。同时，DNMT3Ab在体内促进GC的肺转移。机制研究表明，DNMT3Ab通过H3K9me2和H3K27me3的DNA超甲基化和组蛋白修饰介导E-cadherin基因的表观遗传不作为。DNMT3Ab的缺失通过降低E-cadherin启动子DNA甲基化、H3K9me2和H3K27me3水平，有效恢复E-cadherin的表达，逆转TGF-β诱导的EMT。重要的是，DNMT3Ab与H3K9me2和H3K27me3合作，以蜗牛依赖的方式参与E-cadherin的转录调控。此外，基因表达谱分析表明，多种转移相关基因和致癌信号通路受到DNMT3Ab过表达的调控。这些结果表明DNMT3Ab是胃癌转移相关基因的关键调节因子。靶向DNMT3Ab/Snail/E-cadherin轴可能为治疗高DNMT3Ab表达的转移性胃癌提供了一种有希望的治疗策略。
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.
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DOI：
10.1016/j.bbrc.2009.07.093
发表时间：
2009-09-25
影响因子：
3.1
作者：
Deng, Tao;Kuang, Ying;Fei, Jian
通讯作者：
Fei, Jian
影响因子：
2.7
作者：
La Salle, Sophie;Trasler, Jacquetta M.
通讯作者：
Trasler, Jacquetta M.
影响因子：
6.2
作者：
Jung, Hun;Lee, Han Hong;Park, Cho Hyun
通讯作者：
Park, Cho Hyun
影响因子：
11
作者：
Oliveira, A. M. M.;Hemstedt, T. J.;Bading, H.
通讯作者：
Bading, H.
影响因子：
9
作者：
Kim BG;Gao MQ;Kang S;Choi YP;Lee JH;Kim JE;Han HH;Mun SG;Cho NH
通讯作者：
Cho NH