SIRT2‐dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases. (5th March 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO reports. Volume 21:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-05
• Subjects: acetylation -- colorectal cancer -- IDH1 -- metastasis -- SIRT2; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948183
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: SIRT2 inhibits colorectal cancer cell invasion and metastasis by regulating IDH1 acetylation on K224. SIRT2 deacetylates IDH1 on Lys224 in colorectal cancer. IDH1 K224 acetylation activates HIF1α/SRC axis to promote colorectal cancer metastasis. IDH1 acetylation predicts poor prognosis in colorectal cancer. Abstract : SIRT2 inhibits colorectal cancer cell invasion and metastasis by regulating IDH1 acetylation on K224.