IDH1 K224 acetylation promotes colorectal cancer via miR-9-5p/NHE1 axis-mediated regulation of acidic microenvironment.
IDH1 K224 acetylation promotes colorectal cancer via miR-9-5p/NHE1 axis-mediated regulation of acidic microenvironment.
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IDH1 K224乙酰化通过miR-9-5p/NHE1轴介导的酸性微环境调节促进结直肠癌。
DOI：
10.1016/j.isci.2023.107206
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发表时间：
2023-07-21
期刊：
影响因子：
5.8
通讯作者：
Shen, Zhanlong
中科院分区：
文献类型：
--
作者：
Wang, Bo;Zhao, Long;Yang, Changjiang;Lin, Yilin;Wang, Shan;Ye, Yingjiang;Luo, Jianyuan;Shen, Zhanlong
酸性微环境被认为是结直肠癌恶变的重要因素。然而，潜在的机制仍不清楚。在先前的研究中，我们证实IDH1K224脱乙酰基促进了酶的活性和α-KG的产生。在这里，我们进一步研究IDH1的超乙酰化对结直肠癌酸性微环境的影响。我们证明，增加的α-KG影响AgO2的羟化，并介导针对NHE1蛋白的miR-9-5p。NHE1基因的敲除通过限制细胞内H+向细胞外的运输，显著地减弱了结直肠癌细胞的增殖和迁移。此外，我们还发现miR-9-5p是在IDH1 K224乙酰化变化中差异最显著的microRNA，并且可以下调NHE1的mRNA。我们的数据还表明，羟基化稳定了Ago2，进而促进了miR-9-5p的活性。综上所述，我们的结果揭示了IDH1去乙酰化调节细胞酸性微环境和抑制结直肠癌转移的新机制。α-KG可以影响抗原2的羟化，并介导针对NHE1蛋白的miR-9-5p/AgO2/NHE1轴调节细胞外H+浓度；肿瘤。
The acidic microenvironment is considered an important factor in colorectal cancer (CRC) that contributes to malignant transformation. However, the underlying mechanism remains unclear. In a previous study, we confirmed that IDH1 K224 deacetylation promotes enzymatic activity and the production of α-KG. Here, we further investigate the effect of IDH1 hyperacetylation on the CRC acidic microenvironment. We demonstrate that increased α-KG affects hydroxylation of Ago2 and mediates miR-9-5p targeting NHE1 protein. Knockdown of NHE1 dramatically attenuates CRC cell proliferation and migration by restricting transport of intracellular H+ out of cells. Furthermore, we show that miR-9-5p is the microRNA with the most significant difference in the alteration of IDH1 K224 acetylation and can downregulate NHE1 mRNA. Our data also indicate that hydroxylation stabilizes Ago2, which in turn promotes miR-9-5p activity. Taken together, our results reveal a novel mechanism through which IDH1 deacetylation regulates the cellular acidic microenvironment and inhibits CRC metastasis. IDH1 hyperacetylation mediates the acidic microenvironment of colorectal cancer α-KG can affect hydroxylation of Ago2 and mediates miR-9-5p targeting NHE1 protein MiR-9-5p/Ago2/NHE1 axis regulates extracellular H+ concentration Cell biology; Cancer.
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