Abstract
BackgroundOur previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated.MethodsExpression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model.ResultsWe found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially.ConclusionsCollectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.
Highlights
Our previous study has demonstrated that Nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell
NAD(P)H: quinone oxidoreductase 1 (NQO1) regulates X-linked inhibitor of apoptosis protein (XIAP) phosphorylation via AKT activation As reported in our previous study [8], NQO1 was generally upregulated in Hepatocellular Carcinoma (HCC), which was associated with poor prognosis
It has been reported that XIAP was phosphorylated and stabilized by AKT at Ser87 [31,32,33,34], we analyzed whether NQO1 regulated AKT expression and activation
Summary
Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. Recent studies have showed that NQO1 is upregulated in many human cancers, including. Lung cancer and uterine cervical cancer, high-level NQO1 expression was closely associated with poor differentiation, late clinical stage and lymph node metastasis. Patients with high-level expression of NQO1 had a shorter disease-free survival and overall survival rate than those with low NQO1 expression in cell lung cancer [3]. We have reported that NQO1 is generally increased in HCCs where its high expression level is related with poor patient survival rate. NQO1 potentiates the apoptosis evasion of liver cancer cell through upregulating X-
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