Abstract
Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCCs, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin through its ability to positively regulate XPC-dependent GG-NER following DNA damage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Carcinoma, Squamous Cell / etiology
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / pathology
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Cell Line / metabolism
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Cell Line / pathology
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Cell Line / radiation effects
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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DNA Damage*
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DNA Repair / genetics
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DNA Repair / physiology*
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DNA-Binding Proteins / physiology
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Down-Regulation
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Humans
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Keratinocytes / metabolism
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Keratinocytes / pathology
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Keratinocytes / radiation effects*
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Keratosis, Actinic / genetics*
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Keratosis, Actinic / pathology
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Mice
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Neoplasms, Radiation-Induced / genetics*
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Neoplasms, Radiation-Induced / pathology
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PTEN Phosphohydrolase / antagonists & inhibitors
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PTEN Phosphohydrolase / deficiency
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / physiology*
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Papilloma / etiology
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Papilloma / genetics
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Papilloma / pathology
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Precancerous Conditions / etiology
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Precancerous Conditions / genetics
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Protein Kinases / physiology
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins c-akt / physiology
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RNA, Small Interfering / pharmacology
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Skin Neoplasms / etiology
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Ultraviolet Rays / adverse effects*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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DNA-Binding Proteins
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RNA, Small Interfering
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XPC protein, human
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Protein Kinases
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Checkpoint Kinase 2
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AKT1 protein, human
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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Pten protein, mouse