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Stress-induced NQO1 controls stability of C/EBP? against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

ABSTRACT: Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT-enhancer binding protein (C/EBP?) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis revealed that disruption of the NQO1 gene in mice and mouse keratinocytes led to degradation of C/EBP? and loss of p63 gene expression. p63 promoter mutagenesis, transfection and chromatin immunoprecipitation assays identified a C/EBP?-binding site between nucleotide position -185 and -174 that bound to C/EBP? and upregulated p63 gene expression. Co-immunoprecipitation and immunoblot analysis demonstrated that 20S proteasomes directly interacted and degraded C/EBP?. NQO1 direct interaction with C/EBP? led to stabilization of C/EBP? against 20S proteasomal degradation. NQO1 protection of C/EBP? required binding of NADH with NQO1. Exposure of skin and keratinocytes to the chemical stress agent benzo(a)pyrene led to induction of NQO1 and stabilization of C/EBP? protein, resulting in an increase in p63 RNA and protein in wild-type but not in NQO1-/- mice. Collectively, the current data combined with previous data suggest that stress induction of NQO1 through both stabilization of C/EBP? and increase in p63 and direct stabilization of p63 controls keratinocyte differentiation, leading to protection against chemical-induced skin carcinogenesis. The studies are significant as 2-4% human individuals are homozygous and 23% are heterozygous for the NQO1P187S mutation and might be susceptible to stress-induced skin diseases.

SUBMITTER: Patrick BA

PROVIDER: S-EPMC3538879 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

Patrick B A BA Jaiswal A K AK

Oncogene 20120116 40

Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT-enhancer binding protein (C/EBPα) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis ...[more]

PMID: 22249251

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Project description:Hyperproliferating cancer cells produce energy mainly from aerobic glycolysis, which results in elevated ROS levels. Thus aggressive tumors often possess enhanced anti-oxidant capacity that impedes many current anti-cancer therapies. Additionally, in ROS-compromised cancer cells ubiquitin proteasome system (UPS) is often deregulated for timely removal of oxidized proteins, thus enabling cell survival. Taken that UPS maintains the turnover of factors controlling cell cycle and apoptosis--such as p53 or p73, it represents a promising target for pharmaceutical intervention. Enhancing oxidative insult in already ROS-compromised cancer cells appears as an attractive anti-tumor scenario. TAp73 is a bona fide tumor suppressor that drives the chemosensitivity of some cancers to cisplatin or γ-radiation. It is an important drug target in tumors where p53 is lost or mutated. Here we discovered a novel synergistic mechanism leading to potent p73 activation and cancer cell death by oxidative stress and inhibition of 20S proteasomes. Using a small-molecule inhibitor of 20S proteasome and ROS-inducer--withaferin A (WA), we found that WA-induced ROS activates JNK kinase and stabilizes phase II anti-oxidant response effector NF-E2-related transcription factor (NRF2). This results in activation of Nrf2 target--NQO1 (NADPH quinone oxidoreductase), and TAp73 protein stabilization. The observed effect was ablated by the ROS scavenger--NAC. Concurrently, stress-activated JNK phosphorylates TAp73 at multiple serine and threonine residues, which is crucial to ablate TAp73/MDM2 complex and to promote TAp73 transcriptional function and induction of robust apoptosis. Taken together our data demonstrate that ROS insult in combination with the inhibition of 20S proteasome and TAp73 activation endows synthetic lethality in cancer cells. Thus, our results may enable the establishment of a novel pharmacological strategy to exploit the enhanced sensitivity of tumors to elevated ROS and proteasomal stress to kill advanced tumors by pharmacological activation of TAp73 using molecules like WA.

Dataset Information

Stress-induced NQO1 controls stability of C/EBP? against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

Publications

Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

Similar Datasets

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