NQO1 Suppresses NF-κB–p300 Interaction to Regulate Inflammatory Mediators Associated with Prostate Tumorigenesis

Thapa, Dinesh; Meng, Peng; Bedolla, Roble; Reddick, Robert L.; Kumar, Addanki P.; Ghosh, Rita

doi:10.1158/0008-5472.can-14-0562

Cited by 42 publications

(44 citation statements)

References 50 publications

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“…33). In addition, it has been reported that NQO1 suppresses NF-κB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis52. These studies suggested that NQO1 could act to suppress tumorigenesis in certain conditions.…”

Section: Discussionmentioning

confidence: 96%

NQO1 inhibits proteasome-mediated degradation of HIF-1α

et al. 2016

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Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.

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Section: Discussionmentioning

confidence: 96%

NQO1 inhibits proteasome-mediated degradation of HIF-1α

et al. 2016

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“…Increased 8‐oxoG with age and in CaP has been found by different methods in tissues, urine and serum (Malins et al., 2001; Miyake et al., 2004; Kosova et al., 2014). Also, a role of NQO1 in blocking CaP progression has been recently proposed for the mouse TRAMP CaP model (Thapa et al., 2014). Furthermore, NQO1 silencing in CaP cells enhanced the levels of nuclear IKKalpha and NF‐kB while decreasing the levels of p53, leading to interactions between NF‐kB and p300 that reinforce cellular pro‐survival signalling (Thapa et al, 2014; Bouchal et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

et al. 2016

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The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.

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“…Actually, NQO1 has positive effects on malignant cells that are already in neoplastic state 22-24, but, as a part of senescence barrier, NQO1 also exhibits anti-tumorigenicity properties during the malignant progression by which normal cells evolve to cancer cells.…”

Section: Discussionmentioning

confidence: 99%

NQO1 Stabilizes p53 in Response to Oncogene-Induced Senescence

Liu¹,

Jin²,

Wu³

et al. 2015

Int. J. Biol. Sci.

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Cellular senescence is a state of permanent cellular arrest that provides an initial barrier to cell transformation and tumorigenesis. In this study, we report that expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a cytoplasmic 2-electron reductase, is induced during oncogene-induced senescence (OIS). Depletion of NQO1 resulted in the delayed onset of senescence. In contrast, ectopic expression of NQO1 enhanced the senescence phenotype. Analysis of the mechanism underlying the up-regulation of NQO1 expression during senescence identified that NQO1 promotes p53 accumulation in an MDM2 and ubiquitin independent manner, which reinforces the cellular senescence phenotype. Specifically, we demonstrated that NRF2/KEAP1 signaling regulates NQO1 expression during OIS. More importantly, we confirmed that depletion of NQO1 facilitates cell transformation and tumorigenesis, which indicates that NQO1 takes part in the senescence barrier and has anti-oncogenic properties in cell transformation.

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NQO1 Suppresses NF-κB–p300 Interaction to Regulate Inflammatory Mediators Associated with Prostate Tumorigenesis

Cited by 42 publications

References 50 publications

NQO1 inhibits proteasome-mediated degradation of HIF-1α

NQO1 inhibits proteasome-mediated degradation of HIF-1α

DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

NQO1 Stabilizes p53 in Response to Oncogene-Induced Senescence

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