SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases
SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases
复制标题
SIRT2 依赖性 IDH1 脱乙酰化可抑制结直肠癌和肝转移。
DOI：
10.15252/embr.201948183
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发表时间：
2020-03-05
期刊：
影响因子：
7.7
通讯作者：
Shen, Zhanlong
中科院分区：
文献类型：
--
作者：
Wang, Bo;Ye, Yingjiang;Shen, Zhanlong
蛋白质赖氨酸乙酰化通过多种途径影响结直肠癌（CRC）的远处转移。在以前的蛋白质组学筛选中，我们发现异柠檬酸脱氢酶1（IDH 1）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IDH 1在赖氨酸224处的超乙酰化在CRC进展中的作用。我们发现IDH 1 K224脱乙酰化促进了其酶活性和α-KG的产生，并且我们鉴定了sirtuin-2（SIRT 2）作为IDH 1的主要脱乙酰酶。SIRT 2过表达显著抑制CRC细胞增殖、迁移和侵袭。IDH 1乙酰化响应于细胞内代谢物浓度而调节，并调节细胞氧化还原止血。此外，IDH 1乙酰化调节HIF 1 α依赖性SRC转录，进而控制CRC进展。在生理学上，我们的数据表明IDH 1去乙酰化在体外和体内抑制CRC细胞的侵袭和迁移，而K224上IDH 1的过度乙酰化与结直肠癌患者的远处转移和不良生存率显著相关。总之，我们的研究揭示了SIRT 2依赖性IDH 1去乙酰化调节细胞代谢和抑制结直肠癌肝转移的新机制。
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 alpha-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 HIF1 alpha-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.