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STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis.
Oncogenesis ( IF 6.2 ) Pub Date : 2020-02-10 , DOI: 10.1038/s41389-020-0195-2
Hongyan Qi 1 , Zhiyi Yang 2 , Chujun Dai 2 , Runan Wang 2 , Xinxin Ke 2 , Shuilian Zhang 2 , Xueping Xiang 3 , Kailin Chen 2 , Chen Li 4 , Jindan Luo 5 , Jimin Shao 6 , Jing Shen 2
Affiliation  

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.

中文翻译:

STAT3激活MSK1介导的组蛋白H3磷酸化,以促进胃癌发生中的NFAT信号传导。

表观遗传异常显着促进胃癌的发展和进展。但是,从致癌信号途径到表观遗传失调的潜在调控网络仍然不清楚。在这里,我们显示出STAT3信号传导(炎症和癌症之间的关键联系之一)在胃癌发生过程中充当了控制途径。STAT3异常激活表观遗传激酶的促分裂原和应激激活的蛋白激酶1(MSK1),从而在致癌物诱导的胃肿瘤发生过程中使组蛋白H3 serine10(H3S10)和STAT3自身磷酸化。我们进一步确定了钙途径转录因子NFATc2作为STAT3-MSK1正调控环的新型下游目标。STAT3在NFATc2的启动子处与MSK1形成功能复合物,以H3S10磷酸化依赖性方式促进其转录,从而影响胃癌发生过程中与NFATc2相关的炎症途径。抑制STAT3 / MSK1 / NFATc2信号轴显着抑制胃癌细胞的增殖和异种移植肿瘤的生长,这通过调节异常的表观遗传和转录机制为胃癌发生干预提供了一种潜在的新方法。
更新日期:2020-02-10
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