Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer
| Autor: | Tian-En Li, Jimeng Yang, Bei-Yuan Hu, Da Xu, Qiongzhu Dong, Chaoqun Wang, Ze Zhang, Feng Yang, Christiane Bruns, Shican Yan, Peter J. Nelson, Min Xue, Yan Zheng, Deliang Fu, Hu-Liang Jia, Yue Zhao, Lun-Xiu Qin, Xuan Wang, Chao Wu |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Linsitinib endocrine system diseases lcsh:Medicine Article Histone Deacetylases Metastasis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genetics medicine Humans Insulin-Like Growth Factor I Neoplasm Metastasis Protein kinase B lcsh:QH301-705.5 PI3K/AKT/mTOR pathway Chemistry lcsh:R HDAC3 medicine.disease Cancer metabolism Neoplasm Proteins Pancreatic Neoplasms Enolase 2 030104 developmental biology PCAF lcsh:Biology (General) Acetylation Phosphopyruvate Hydratase 030220 oncology & carcinogenesis Cancer research Female Signal Transduction |
| Zdroj: | Signal Transduction and Targeted Therapy, Vol 5, Iss 1, Pp 1-14 (2020) Signal Transduction and Targeted Therapy |
| ISSN: | 2059-3635 |
| DOI: | 10.1038/s41392-020-0146-6 |
| Popis: | Enolase 2 (ENO2) is a key glycolytic enzyme in the metabolic process of glycolysis, but its potential function in pancreatic ductal adenocarcinoma (PDAC) is unclear. In this study, we observed a significant overexpression of ENO2 in PDAC tissues, and its expression was correlated with metastasis and poor prognosis in PDAC patients. K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity, cell metabolism and PDAC progression. Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC. Re-expression of wild-type (WT) ENO2, but not the K394 acetylation mimetic mutant, could reverse the decreased tumor malignancy. We further characterized histone deacetylase 3 (HDAC3) and P300/CBP-associated factor (PCAF) as the potential deacetylase and acetyltransferase for ENO2, respectively. HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis. Importantly, insulin-like growth factor-1 (IGF-1) was found to decrease K394 acetylation and stimulate ENO2 activity in a dose- and time-dependent manner. The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424, which promoted K394 deacetylation and activation of ENO2. Linsitinib, an oral small-molecule inhibitor of IGF-1R, could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway. Furthermore, linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394-mutant ENO2. Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis. Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC. |
| Databáze: | OpenAIRE |
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