Abstract
Background: The identification of prognostic markers for non-small-cell lung carcinoma (NSCLC) is needed for clinical practice. The metabolism-reprogramming marker ketohexokinase (KHK)-A and acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659 (ACSS2 pS659) play important roles in tumorigenesis and tumor development. However, the clinical significance of KHK-A and ACSS2 pS659 in NSCLC is largely unknown.Methods: The expression levels of KHK-A and ACSS2 pS659 were assessed by immunohistochemistry analyses of surgical specimens from 303 NSCLC patients. The prognostic values of KHK-A and ACSS2 pS659 were evaluated by Kaplan–Meier methods and Cox regression models.Results: The expression levels of KHK-A and ACSS2 pS659 were significantly higher in NSCLC tissues than those in adjacent non-tumor tissues (P < 0.0001). KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 were inversely correlated with overall survival in NSCLC patients (P < 0.001). The multivariate analysis indicated that KHK-A or ACSS2 pS659 and KHK-A/ACSS2 pS659 were independent prognostic biomarkers for NSCLC (P = 0.008 for KHK-A, P < 0.001 for ACSS2 pS659, and P < 0.001 for KHK-A/ACSS2 pS659). Furthermore, the combination of KHK-A and ACSS2 pS659 can be used as a prognostic indicator for all stages of NSCLC.Conclusions: KHK-A or ACSS2 pS659 alone and the combination of KHK-A and ACSS2 pS659 can be used as prognostic markers for NSCLC. Our findings highlight the important role of metabolic reprogramming in NSCLC progression.
Highlights
Lung cancer is becoming the leading cause of cancer-related death worldwide [1]
We recently reported that a splicing switch from KHK-C to KHK-A occurs in hepatocellular carcinoma (HCC), leading to fructose metabolism reduction, and KHK-A phosphorylates and activates phosphoribosyl pyrophosphate synthetase 1 (PRPS1), resulting in increased de novo nucleic acid synthesis for HCC development [6]
We showed that KHK-A was primary in the cytoplasm of the Non-small-cell lung carcinoma (NSCLC) cells and that acetyl-CoA synthetase 2 (ACSS2) pS659 was observed in both nucleus and cytoplasm of the NSCLC cells (Figures 1A,B)
Summary
Non-small-cell lung carcinoma (NSCLC) is the most common type of lung cancer, accounting for ∼85% of all cases [2]. The reprogramming of energy metabolism is one of the hallmarks of cancer [4]. Cancer cell metabolism and other cellular activities are integrated and mutually regulated [5]. Recent studies have shown that metabolic enzymes, such as ketohexokinase (KHK)-A and acetyl-CoA synthetase 2 (ACSS2), are moderated spatially and temporally in cancer cells so that these enzymes have changes in metabolic activities and gain non-canonical functions [5]. The identification of prognostic markers for non-small-cell lung carcinoma (NSCLC) is needed for clinical practice. The metabolism-reprogramming marker ketohexokinase (KHK)-A and acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659 (ACSS2 pS659) play important roles in tumorigenesis and tumor development. The clinical significance of KHK-A and ACSS2 pS659 in NSCLC is largely unknown
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