Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

• Published in: Signal transduction and targeted therapy 2020-05, Vol.5 (1), p.53-53, Article 53
• Main Authors: Zheng, Yan, Wu, Chao, Yang, Jimeng, Zhao, Yue, Jia, Huliang, Xue, Min, Xu, Da, Yang, Feng, Fu, Deliang, Wang, Chaoqun, Hu, Beiyuan, Zhang, Ze, Li, Tianen, Yan, Shican, Wang, Xuan, Nelson, Peter J., Bruns, Christiane, Qin, Lunxiu, Dong, Qiongzhu
• Format: Article
• Language: English
• Subjects: 631/67/2327; 631/67/322; Cancer Research; Cell Biology; Insulin-like growth factors; Internal Medicine; Medicine; Medicine & Public Health; Metastasis; Oncology; Pancreatic cancer; Pathology
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-020-0146-6

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.