SIRT 2‐dependent IDH 1 deacetylation inhibits colorectal cancer and liver metastases

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