PTEN positively regulates UVB-induced DNA damage repair

Department of Medicine, University of Chicago, Chicago, IL, USA.
Cancer Research (Impact Factor: 9.33). 08/2011; 71(15):5287-95. DOI: 10.1158/0008-5472.CAN-10-4614
Source: PubMed


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.

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    • "It is generally considered that the currently increasing incidence of skin cancers, especially in pale-skinned populations, is a consequence of depletion of the stratospheric ozone layer depletion (Narayanan et al., 2010). Indeed, approximately 96% of the all skin malignancies are non-melanoma skin cancers (NMSC) and ultraviolet B radiation has been identified as the primary risk factor for NMSC (Narayanan et al., 2010; Ming et al., 2011). Thus, development of novel photoprotective agents against ultraviolet B radiation is an urgent need. "
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    ABSTRACT: Usnic acid and atranorin are known as both sunscreen substances in natural lichen population and cytotoxic substances on human cell lines. Both substances were isolated from the acetone extracts of Cladonia foliacea and Pseudevernia furfuracea, respectively. Their photoprotective activities on irradiated human keratinocyte (HaCaT) cells and destructive effects on non-irradiated HaCaT cells were compared by a modified method in order to assess the effects on mitochondrial metabolic activity (MTT assay), membrane integrity (LDH assay), apoptosis (DAPI staining) and cytoskeleton integrity (TRITC-phalloidin staining). This study showed that usnic acid and atranorin have substantial photosensitizing activity, which appears to be linked to their crystallized forms in lichen populations and their decreased amounts in the spring and summer seasons, when ultraviolet B radiation is maximum. However, their cytotoxic, apoptotic and cytoskeleton deleterious activities may be a considerable obstacle for their use in human skin care.
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    • "p38 activity was also found to be reduced in human SCCs, compared to normal human skin [22]. Moreover, inhibition of p38 signaling was associated with a defect in global genome nucleotide excision repair (GG-NER), a vitally important tumor protective pathway that recognizes and excises UVB-induced CPDs (cyclobutane pyrimidine dimers) and 6-4PPs (pyrimidine (6-4) pyrimidone photoproducts) that would otherwise be mutagenic [36]. These data indicate that p38α loss can promote UV-induced skin tumorigenesis. "
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    ABSTRACT: p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage-a primary risk factor for human skin cancers-its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (α/β/γ/δ); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38α, without affecting other isoforms. p38α levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38α in SCC pathogenesis. Genetic and pharmacological inhibition of p38α and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38α deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Concerning regulatory mechanisms upstream of NER, it has been clearly shown that a functional p53 tumour suppressor pathway, triggered following genotoxic insult to regulate apoptosis and growth arrest, is also required for efficient CPD removal in various cell types including melanoma [11], [12]; nonetheless mutational inactivation of p53 appears rare in melanoma [13]. On the other hand the PTEN tumour suppressor, frequently downregulated by genetic or epigenetic means in melanoma [14], has recently been implicated in protection against UVB-induced nonmelanoma skin cancer by positively regulating NER [15]. However the extent to which PTEN might similarly influence UV damage repair in the context of malignant melanoma was not evaluated. "
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    ABSTRACT: It is well established that efficient removal of highly-promutagenic UV-induced dipyrimidine photoproducts via nucleotide excision repair (NER) is required for protection against sunlight-associated malignant melanoma. Nonetheless, the extent to which reduced NER capacity might contribute to individual melanoma susceptibility in the general population remains unclear. Here we show that among a panel of 14 human melanoma strains, 11 exhibit significant inhibition of DNA photoproduct removal during S phase relative to G0/G1 or G2/M. Evidence is presented that this cell cycle-specific NER defect correlates with enhanced apoptosis and reduced clonogenic survival following UV irradiation. In addition, melanoma strains deficient in S phase-specific DNA photoproduct removal manifest significantly lower levels of phosphorylated histone H2AX at 1 h post-UV, suggesting diminished activation of ataxia telangiectasia and Rad 3-related (ATR) kinase, i.e., a primary orchestrator of the cellular response to UV-induced DNA replication stress. Consistently, in the case of DNA photoproduct excision-proficient melanoma cells, siRNA-mediated depletion of ATR (but not of its immediate downstream effector kinase Chk1) engenders deficient NER specifically during S. On the other hand simultaneous siRNA-mediated depletion of ataxia telangiectasia mutated kinase (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) exerts no significant effect on either phosphorylation of H2AX at 1 h post-UV or the efficiency of DNA photoproduct removal. Our data suggest that defective NER exclusively during S phase, possibly associated with decreased ATR signaling, may constitute an heretofore unrecognized determinant in melanoma pathogenesis.
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