Calreticulin enhances gastric cancer metastasis by dimethylating H3K9 in the E-cadherin promoter region mediating by G9a.
Calreticulin enhances gastric cancer metastasis by dimethylating H3K9 in the E-cadherin promoter region mediating by G9a.
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DOI：
10.1038/s41389-022-00405-7
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发表时间：
2022-05-31
期刊：
影响因子：
6.2
通讯作者：
Zheng, Junsong
中科院分区：
文献类型：
--
作者：
Wang, Lina;Chen, Jun;Zuo, Qianfei;Wu, Chunmei;Yu, Ting;Zheng, Pengfei;Huang, Hui;Deng, Jun;Fang, Lichao;Liu, Huamin;Li, Chenghong;Yu, Peiwu;Zou, Quanming;Zheng, Junsong
最新研究显示，2020年，胃癌(GC)以每年超过100万的估计新增病例位居最常见癌症的第五位(5.6%)，并在全球癌症死亡原因中排名第四(7.7%)。转移是GC治疗失败的主要原因。因此，有必要阐明胃癌转移过程的调控机制。本研究发现，钙网蛋白(CALR)在胃癌组织中高表达，并与淋巴结转移和患者预后不良有关。CALR的引入在体内外显著促进了GC细胞的迁移，而对CALR的抑制作用则相反。细胞迁移是上皮-间充质转化(EMT)的功能结果，与细胞的黏附有关。此外，我们还观察到，抑制或过度表达CALR可调节细胞外基质标志物(E-钙粘蛋白、ZO-1、Snail、N-钙粘蛋白和ZEB1)和细胞黏附分子(纤维连接蛋白、整合素β1和MMP2)的表达。在机制上，我们的数据表明CALR可以通过与G9a相互作用来介导E-钙粘素启动子的DNA甲基化。G9a是负责赖氨酸9上组蛋白H3甲基化的主要常染色质甲基转移酶(H3K9me2)，并将G9a招募到E-钙粘素启动子上。在CALR过表达模型中敲除G9a可恢复E-钙粘附素的表达，并阻断CALR对GC细胞迁移的刺激作用。综上所述，这些发现不仅揭示了CALR在胃癌转移中的关键作用，也为胃癌的治疗提供了新的策略。
The latest study shows that gastric cancer (GC) ranked the fifth most common cancer (5.6%) with over 1 million estimated new cases annually and the fourth most common cause of cancer death (7.7%) globally in 2020. Metastasis is the leading cause of GC treatment failure. Therefore, clarifying the regulatory mechanisms for GC metastatic process is necessary. In the current study, we discovered that calreticulin (CALR) was highly expressed in GC tissues and related to lymph node metastasis and patient’s terrible prognosis. The introduction of CALR dramatically promoted GC cell migration in vitro and in vivo, while the repression of CALR got the opposite effects. Cell migration is a functional consequence of the epithelial-mesenchymal transition (EMT) and is related to adhesion of cells. Additionally, we observed that CALR inhibition or overexpression regulated the expression of EMT markers (E-cadherin, ZO-1, Snail, N-cadherin, and ZEB1) and cellular adhesive moleculars (Fibronectin, integrin β1and MMP2). Mechanistically, our data indicated that CALR could mediate DNA methylation of E-cadherin promoter by interacting with G9a, a major euchromatin methyltransferase responsible for methylation of histone H3 on lysine 9(H3K9me2) and recruiting G9a to the E-cadherin promoter. Knockdown of G9a in CALR overexpressing models restored E-cadherin expression and blocked the stimulatory effects of CALR on GC cell migration. Taken together, these findings not only reveal critical roles of CALR medicated GC metastasis but also provide novel treatment strategies for GC.
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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
影响因子：
8
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
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影响因子：
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64.8
作者：
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通讯作者：
MICHALAK, M
影响因子：
8
作者：
Lee, S. H.;Kim, J.;Lee, Y. M.
通讯作者：
Lee, Y. M.
影响因子：
3.7
作者：
Lee, Po-Chu;Chiang, Jui-Chung;Lee, Hsinyu
通讯作者：
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