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SIRT 2‐dependent IDH 1 deacetylation inhibits colorectal cancer and liver metastases
Author(s) -
Wang Bo,
Ye Yingjiang,
Yang Xin,
Liu Boya,
Wang Zhe,
Chen Shuaiyi,
Jiang Kewei,
Zhang Wei,
Jiang Hongpeng,
Mustonen Harri,
Puolakkainen Pauli,
Wang Shan,
Luo Jianyuan,
Shen Zhanlong
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948183
Subject(s) - acetylation , cancer research , sirt2 , colorectal cancer , metastasis , isocitrate dehydrogenase , biology , sirtuin , sirtuin 1 , cell growth , cancer , downregulation and upregulation , biochemistry , enzyme , genetics , gene
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.