Loss of Nrf2 abrogates the protective effect of Keap1 down regulation in a preclinical model of cutaneous squamous cell carcinoma

Elena V. Knatko; Maureen Higgins; Jed W. Fahey; Albena Dinkova-Kostova

doi:10.1038/srep25804

Loss of Nrf2 abrogates the protective effect of Keap1 down regulation in a preclinical model of cutaneous squamous cell carcinoma

Elena V. Knatko, Maureen Higgins, Jed W. Fahey, Albena Dinkova-Kostova (Lead / Corresponding author)

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Abstract

Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2-/- ) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2-/- mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.

Original language	English
Article number	25804
Number of pages	7
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep25804
Publication status	Published - 24 May 2016

Keywords

chemoprevention
cutaneous squamous cell carcinoma
Keap1
Nrf2
UV radiation

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Dinkova-Kostova, Albena
- Cancer Research - Professor (Teaching and Research) of Chemical Biology
Person: Academic

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title = "Loss of Nrf2 abrogates the protective effect of Keap1 down regulation in a preclinical model of cutaneous squamous cell carcinoma",

abstract = "Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2-/- ) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2-/- mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.",

keywords = "chemoprevention, cutaneous squamous cell carcinoma, Keap1, Nrf2, UV radiation",

author = "Knatko, {Elena V.} and Maureen Higgins and Fahey, {Jed W.} and Albena Dinkova-Kostova",

note = "Funding: Cancer Research UK (C20953/A10270 and C20953/A18644) for financial support.",

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journal = "Scientific Reports",

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T1 - Loss of Nrf2 abrogates the protective effect of Keap1 down regulation in a preclinical model of cutaneous squamous cell carcinoma

AU - Knatko, Elena V.

AU - Higgins, Maureen

AU - Fahey, Jed W.

AU - Dinkova-Kostova, Albena

N1 - Funding: Cancer Research UK (C20953/A10270 and C20953/A18644) for financial support.

PY - 2016/5/24

Y1 - 2016/5/24

N2 - Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2-/- ) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2-/- mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.

AB - Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2-/- ) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2-/- mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.

KW - chemoprevention

KW - cutaneous squamous cell carcinoma

KW - Keap1

KW - Nrf2

KW - UV radiation

U2 - 10.1038/srep25804

DO - 10.1038/srep25804

M3 - Article

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SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 25804

ER -

Loss of Nrf2 abrogates the protective effect of Keap1 down regulation in a preclinical model of cutaneous squamous cell carcinoma

Abstract

Keywords

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Dinkova-Kostova, Albena

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