Abstract
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.
Highlights
Pancreatic cancer is one of the most rapidly lethal cancers
Enolase 2 (ENO2) correlates with metastasis and prognosis of pancreatic ductal adenocarcinoma (PDAC) To investigate the possible role of ENO2 in pancreatic cancer progression, we first analyzed ENO2 mRNA levels based on two Gene Expression Omnibus (GEO) datasets (GSE28735 and GSE15471)
In comparison with that in nonmetastatic PDAC tissues, the protein level of ENO2 was found to be increased in PDAC tissues with liver metastasis (Fig. 1f), suggesting that ENO2 may be involved in PDAC progression
Summary
Pancreatic cancer is one of the most rapidly lethal cancers. Recent data show that the 5-year survival of patients with pancreatic carcinoma remains as low as 5–15% worldwide.[1,2] To date, pancreatic ductal adenocarcinoma (PDAC) is the most common subtype of pancreatic carcinoma, accounting for 85% of all pancreatic neoplasms[3] and presenting with a very poor prognosis.With the development of new therapeutic strategies, the mortality rate of some common malignancies is decreasing, but the mortality of PDAC is still high.[1]. Pancreatic cancer is one of the most rapidly lethal cancers. Recent data show that the 5-year survival of patients with pancreatic carcinoma remains as low as 5–15% worldwide.[1,2] To date, pancreatic ductal adenocarcinoma (PDAC) is the most common subtype of pancreatic carcinoma, accounting for 85% of all pancreatic neoplasms[3] and presenting with a very poor prognosis. With the development of new therapeutic strategies, the mortality rate of some common malignancies is decreasing, but the mortality of PDAC is still high.[1] One of the major hallmarks of PDAC is metastasis. Over 50% of patients are diagnosed with local lymph node or distant organ metastasis, and they lose the opportunity for surgical treatment.[4] deciphering the mechanisms underlying PDAC metastasis may allow early intervention and improve the prognosis of this disease
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