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- Title
NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma.
- Authors
Zhou, Hong-Zhong; Zeng, Han-Qing; Yuan, Ding; Ren, Ji-Hua; Cheng, Sheng-Tao; Yu, Hai-Bo; Ren, Fang; Wang, Qing; Qin, Yi-Ping; Huang, Ai-Long; Chen, Juan
- Abstract
Background: 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. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. Methods: Expression 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. Results: We 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. Conclusions: Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.
- Subjects
HEPATOCELLULAR carcinoma; LIVER cells; LIVER cancer; CANCER cells; TUMOR growth; PROTEIN stability
- Publication
Cell Communication & Signaling, 2019, Vol 17, Issue 1, p1
- ISSN
1478-811X
- Publication type
Article
- DOI
10.1186/s12964-019-0491-7