STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis
Autor: | Jindan Luo, Hongyan Qi, Kailin Chen, Xinxin Ke, Shuilian Zhang, Xueping Xiang, Chujun Dai, Jimin Shao, Runan Wang, Zhiyi Yang, Jing Shen, Chen Li |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research NFAT Biology medicine.disease_cause lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens lcsh:RC254-282 Article 03 medical and health sciences Histone H3 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Mitogen-activated protein kinase medicine biology.protein Cancer research Epigenetics Protein kinase A Carcinogenesis STAT3 Gastric cancer Molecular Biology Transcription factor |
Zdroj: | Oncogenesis Oncogenesis, Vol 9, Iss 2, Pp 1-16 (2020) |
ISSN: | 2157-9024 |
Popis: | 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. |
Databáze: | OpenAIRE |
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