转化生长因子β受体I-异柠檬酸脱氢酶1-小窝蛋白1轴促进癌症相关成纤维细胞中的转化生长因子-β信号传导。
TGFBR-IDH1-Cav1 axis promotes TGF-β signalling in cancer-associated fibroblast.
作者信息
Hou Xiaodan, Zhang Jieying, Wang Yongbin, Xiong Wujun, Mi Jun
机构信息
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Center of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou Institute of Systems Medicine, Suzhou, China.
出版信息
Oncotarget. 2017 Sep 13;8(48):83962-83974. doi: 10.18632/oncotarget.20861. eCollection 2017 Oct 13.
TGF-β signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF- β signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-β signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of α-ketoglutarate (α-KG) by accelerating glutamine metabolization. Interestingly, α-KG suppressed Cav1 expression through reducing the trimethylation of histone H3K4. Furthermore, Cav1 downregulation inhibited TGFBR protein degradation. In turn, the activated TGFBR promoted TGF-β signalling. These findings demonstrated that metabolic enzyme IDH1 regulates TGF-β signalling by feedback mechanism through α-KG and TGFBR-IDH1-Cav1 axis is important for TGF-β signalling.
转化生长因子-β（TGF-β）信号通路在成纤维细胞激活和肿瘤进展中起重要作用。在此，我们报告TGFBR-IDH1-Cav1轴促进成纤维细胞中的TGF-β信号通路。我们的数据表明，在成纤维细胞中，TGF-β信号通路下调了IDH1，而IDH1的下调通过加速谷氨酰胺代谢增加了α-酮戊二酸（α-KG）的细胞浓度。有趣的是，α-KG通过减少组蛋白H3K4的三甲基化来抑制Cav1表达。此外，Cav1的下调抑制了TGFBR蛋白的降解。反过来，激活的TGFBR促进了TGF-β信号通路。这些发现表明，代谢酶IDH1通过α-KG以反馈机制调节TGF-β信号通路，且TGFBR-IDH1-Cav1轴对TGF-β信号通路很重要。
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