STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis
STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis
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STAT3激活MSK1介导的组蛋白H3磷酸化促进胃癌发生中的NFAT信号传导
DOI：
10.1038/s41389-020-0195-2
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发表时间：
2020-02-10
期刊：
影响因子：
6.2
通讯作者：
Shen, Jing
中科院分区：
文献类型：
--
作者：
Qi, Hongyan;Yang, Zhiyi;Shen, Jing
表观遗传异常在胃癌的发生、发展中起重要作用。然而，从致癌信号通路到表观遗传失调的潜在调控网络仍然很不清楚。在这里，我们发现，STAT 3信号，炎症和癌症之间的关键环节之一，作为胃癌发生的控制途径。STAT 3异常反式激活表观遗传激酶丝裂原和应激激活蛋白激酶1（MSK 1），从而在致癌物诱导的胃肿瘤发生过程中磷酸化组蛋白H3丝氨酸10（H3 S10）和STAT 3本身。我们进一步确定了钙通道转录因子NFATc 2作为STAT 3-MSK 1正调控环的新下游靶点。STAT 3与MSK 1在NFATc 2的启动子处形成功能复合物，以H3 S10磷酸化依赖的方式促进其转录，从而影响胃癌发生中NFATc 2相关的炎症通路。抑制STAT 3/MSK 1/NFATc 2信号轴可显著抑制胃癌细胞增殖和异种移植瘤生长，这为通过调控异常的表观遗传和转录机制干预胃癌的发生提供了潜在的新途径。
Epigenetic abnormalities contribute significantly to the development and progression of gastric cancer. However, the underlying regulatory networks from oncogenic signaling pathway to epigenetic dysregulation remain largely unclear. Here we showed that STAT3 signaling, one of the critical links between inflammation and cancer, acted as a control pathway in gastric carcinogenesis. STAT3 aberrantly transactivates the epigenetic kinase mitogen- and stress-activated protein kinase 1 (MSK1), thereby phosphorylating histone H3 serine10 (H3S10) and STAT3 itself during carcinogen-induced gastric tumorigenesis. We further identified the calcium pathway transcription factor NFATc2 as a novel downstream target of the STAT3-MSK1 positive-regulating loop. STAT3 forms a functional complex with MSK1 at the promoter of NFATc2 to promote its transcription in a H3S10 phosphorylation-dependent way, thus affecting NFATc2-related inflammatory pathways in gastric carcinogenesis. Inhibiting the STAT3/MSK1/NFATc2 signaling axis significantly suppressed gastric cancer cell proliferation and xenograft tumor growth, which provides a potential novel approach for gastric carcinogenesis intervention by regulating aberrant epigenetic and transcriptional mechanisms.