Abstract
Abstract Signal transducer and activator of transcription (STATs) signaling, particularly STAT3, have been demonstrated to be one of the central pathways for cancer initiation and progression. However, the functional role of STAT3 in regulation of epigenetic changes in cancer, such as histone modifications, remains unclear. Our present study performed on N-nitroso compounds (NOC) induced gastric epithelial cell transformation revealed a positive correlation of active STAT3 signaling with increased histone H3 phosphorylation. Further analysis showed that mitogen- and-stress activated protein kinase (MSK1) was upregulated by NOC treatment, thereby promoting H3 Ser 10 phosphorylation (H3S10P). Intriguingly, putative STAT3 binding sites were identified in the MSK1 promoter, and we finally confirmed that MSK1 is a novel target gene of STAT3. It has been reported that STAT3 is a direct substrate for MSK1. Therefore, we analyzed the status of STAT3 activation after MSK1 overexpression and knockdown, and a positive feedback loop was found between them. With specific siRNA or inhibitors, we further demonstrated the aberrant activation of STAT3/MSK1/H3S10P axis in MNU-induced gastric cancer (GC) model in mice, human gastric cancer cells, and GC patients. ChIP-seq analysis was performed to determine the H3S10 phosphorylation distribution pattern in NOC-transformed gastric epithelial cells, and some candidate regulated genes were successfully identified. Together, the results of these studies shed light onto a critical role of STAT3 signaling in epigenetic modification network, mediated at least in part by MSK1. Our results suggest that STAT3/MSK1/H3S10P pathway and downstream key effectors represent interesting therapeutic targets in gastric carcinogenesis. Citation Format: Hongyan Qi, Zhiyi Yang, Shuilian Zhang, Xinxin Ke, Chujun Dai, Jimin Shao, Jing Shen. STAT3 signaling activates MSK1-mediated histone H3 phosphorylation in N-nitrosocompounds induced carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5051.
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