Protein lysine acetylation affects colorectal cancer (CRC) distant metastasis through multiple pathways. In a previous proteomics screen, we found that isocitrate dehydrogenase 1 (IDH1) is hyperacetylated in CRC primary tumors and liver metastases. Here, we further investigate the function of IDH1 hyperacetylation at lysine 224 in CRC progression. We find that IDH1 K224 deacetylation promotes its enzymatic activity and the production of α-KG, and we identify sirtuin-2 (SIRT2) as a major deacetylase for IDH1. SIRT2 overexpression significantly inhibits CRC cell proliferation, migration, and invasion. IDH1 acetylation is modulated in response to intracellular metabolite concentration and regulates cellular redox hemostasis. Moreover, IDH1 acetylation reversely regulates HIF1α-dependent SRC transcription which in turn controls CRC progression. Physiologically, our data indicate that IDH1 deacetylation represses CRC cell invasion and migration in vitro and in vivo, while the hyperacetylation of IDH1 on K224 is significantly correlated to distant metastasis and poor survival of colorectal cancer patients. In summary, our study uncovers a novel mechanism through which SIRT2-dependent IDH1 deacetylation regulates cellular metabolism and inhibits liver metastasis of colorectal cancer.

中文翻译：

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SIRT2 依赖性 IDH1 去乙酰化抑制结直肠癌和肝转移。

蛋白质赖氨酸乙酰化通过多种途径影响结直肠癌 (CRC) 远处转移。在之前的蛋白质组学筛选中，我们发现异柠檬酸脱氢酶 1 (IDH1) 在 CRC 原发性肿瘤和肝转移瘤中高度乙酰化。在这里，我们进一步研究了 CRC 进展中赖氨酸 224 处 IDH1 高乙酰化的功能。我们发现 IDH1 K224 去乙酰化促进了其酶活性和 α-KG 的产生，我们确定 sirtuin-2 (SIRT2) 是 IDH1 的主要去乙酰化酶。SIRT2 过表达显着抑制 CRC 细胞增殖、迁移和侵袭。IDH1 乙酰化响应细胞内代谢物浓度而受到调节，并调节细胞氧化还原止血。此外，IDH1 乙酰化反向调节 HIF1α 依赖性 SRC 转录，进而控制 CRC 进展。生理学上，我们的数据表明 IDH1 去乙酰化在体外和体内抑制 CRC 细胞侵袭和迁移，而 IDH1 在 K224 上的高乙酰化与结直肠癌患者的远处转移和较差的生存率显着相关。总之，我们的研究揭示了一种新的机制，SIRT2 依赖的 IDH1 去乙酰化调节细胞代谢并抑制结直肠癌的肝转移。