Loss of ARF Sensitizes Transgenic BRAFV600E Mice to UV-Induced Melanoma via Suppression of XPC
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Abstract
Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAF(V600E) is the most prevalent oncogene in melanoma, the BRAF(V600E) mutant is not sufficient to induce tumors in vivo. Mutation at the CDKN2A locus is another melanoma-predisposing event that can disrupt the function of both p16(INK4a) and ARF. Numerous studies have focused on the role of p16(INK4a) in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAF(V600E) mouse model previously generated in our laboratory, we report that loss of ARF is able to enhance spontaneous melanoma formation and cause profound sensitivity to neonatal UVB exposure. Mechanistically, BRAF(V600E) and ARF deletion synergize to inhibit nucleotide excision repair by epigenetically repressing XPC and inhibiting the E2F4/DP1 complex. We suggest that the deletion of ARF promotes melanomagenesis not by abrogating p53 activation but by acting in concert with BRAF(V600E) to increase the load of DNA damage caused by UVR.
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BRAFV600E mutation can synergize with Arf deletion to accelerate UV-induced melanoma development in vivo.
“BRAFV600E mutation in melanocytes can also synergize with Arf deletion in vivo to accelerate UV-induced melanoma development28.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [28]
In a mouse model with Arf deletion and BRAFV600E expression, UVB exposure accelerates melanomagenesis by inhibiting NER.
“In a genetically engineered mouse model of melanoma featuring deletion of Arf and expression of BRAFV600E, UVB exposure accelerated melanomagenesis by inhibiting NER28.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [28]
In that model, Arf deletion induces XPC promoter hypermethylation and repression, as well as E2F4/DP1 inhibition.
“Further analysis concluded that Arf deletion induces XPC promoter hypermethylation and repression, as well as E2F4/DP1 inhibition in this model28.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [28]
BRAFV600E mutation alone is sufficient to repress UVB-induced XPC.
“BRAFV600E mutation alone was also sufficient to repress UVB-induced XPC28.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [28]
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References 50 · Cited by 31
- Authors
- Luo, C., Sheng, J., Hu, M. G., Haluska, F. G., Cui, R., Xu, Z., Tsichlis, P. N., Hu, G.-F., & Hinds, P. W.
- Affiliations
- Boston University (US)
- Corresponding author
- Hinds, Philip W.
- ORCID
- Venue
- Cancer Research
- Published
- 2013-07-15
- Volume
- 73
- Issue
- 14
- Pages
- 4337-4348
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3715591
- OpenAlex
- W2001743422
- Cited by
- 31
- References
- 50
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 3
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- China Scholarship Council
- National Institutes of Health
- National Institute on Aging (R01AG020208, AG020208)
- National Cancer Institute (R01CA095798, CA095798, R01CA096527)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- ARF, BRAF V600E mutation, melanoma, XPC, nucleotide excision repair, epigenetic repression, CDKN2A, p53 activation, melanomagenesis, DNA damage, transgenic mouse model
- MeSH terms
- Animals, Cells, Cultured, DNA Repair, DNA-Binding Proteins, Humans, Melanoma, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Radiation-Induced, Promoter Regions, Genetic, Ultraviolet Rays, Tumor Suppressor Protein p53, Mice, Knockout, DNA Methylation, Cyclin-Dependent Kinase Inhibitor p16, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Transcription Factor DP1, E2F4 Transcription Factor, Mice
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