NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

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.

Gene signatures and prognostic values of m1A-related regulatory genes in hepatocellular carcinoma

“…We speculate that m1A-related regulatory gene alterations may be related to changes in other disease-causing molecules in HCC. Since TP53, NQO1, and EPHX1 play critical roles in HCC pathogenesis [26][27][28] , we assessed the relationship between m1A-related regulatory gene alterations and changes to genes encoding these proteins. Mutations to m1A-related regulatory genes were not significantly correlated with NQO1 and EPHX1, but prominently associated with alterations in TP53.…”

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

“…Studies indicate that PPARg is regulated by selective proteasomal degradation (Hauser et al, 2000;Kim et al, 2014;Li et al, 2017). Along similar lines, SIRT6 regulates p27 and X-linked inhibitor of apoptosis protein (XIAP) levels by modulating their proteasomal degradation (Zhao et al, 2016;Zhou et al, 2019). In addition, PPARg mRNA stability is regulated by the action of different microRNAs (miRNAs) (Portius et al, 2017).…”

Expression of NAD(P)H:Quinone Oxidoreductase 1 and Its Significance in Human Abdominal Aortic Aneurysmal Tissues

“…The overexpression of NRF2/NQO1 in hepatocellular carcinoma was associated with tumor size, high α-fetoprotein, DES-γcarboxy-prothrombin levels and multiple intrahepatic recurrences, could as an independent risk factor [14]. It has been found that the potential mechanism of NQO1 promoting cancer cell proliferation is mainly through the activation of SIRT6/AKT/XIAP signal pathway [15] or by regulating the activity of STRI2 to regulate the process of mitosis [16]. In this study, it was found that NQO1 expression was positively correlated with AAA size and ROS level.…”