The DNA Damage-Binding Protein XPC Is a Frequent Target for Inactivation in Squamous Cell Carcinomas

Feraudy, Sébastien de; Ridd, Katie; Richards, Lauren M.; Kwok, Pui‐Yan; Revet, Ingrid; Oh, Dennis H.; Feeney, Luzviminda; Cleaver, James E.

doi:10.2353/ajpath.2010.090925

Cited by 30 publications

(35 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following UVB exposure, the overall male and female shared genetic response observed at 16 kJ/m 2 is consistent with previous data reported in mammals and fish including modulation of known UVB responsive genes such as cdkn1a, xpc, egr1, gadd45a , and circadian rhythm genes, clock and per2 (de Feraudy et al, 2010; Matsumoto et al, 2015; Meador et al, 2007; Sherr and Roberts, 1999; Yang et al, 2014). Both females and males show a greater genetic response at 16 kJ/m 2 than at 8 kJ/m 2 .…”

Section: Discussionsupporting

confidence: 90%

Sex-specific molecular genetic response to UVB exposure in Xiphophorus maculatus skin

Boswell

Titus

et al. 2015

Comparative Biochemistry and Physiology Part C: Toxicology &

View full text Add to dashboard Cite

In both Xiphophorus fishes and humans, males are reported to have a higher incidence of melanoma than females. To better understand sex specific differences in the molecular genetic response to UVB, we performed RNA-Seq experiments in skin of female and male Xiphophorus maculatus Jp 163 B following UVB doses of 8 or 16 kJ/m2 exposure. Male X. maculatus differentially express a significantly larger number of transcripts following exposure to 16 kJ/m2 UVB (1,293 genes) compared to 8 kJ/m2 UVB (324 genes). Female skin showed differential gene expression in a larger number of transcripts following 8 kJ/m2 UVB (765) than did males; however, both females and males showed similar numbers of differentially expressed genes at 16 kJ/m2 UVB (1,167 and1,293, respectively). Although most modulated transcripts after UVB exposure represented the same dominant pathways in both females and males (e.g., DNA repair, circadian rhythm, and fatty acid biosynthesis), we identified genes in several pathways that exhibited opposite modulation in female vs. male skin (e.g., synaptic development, cell differentiation, wound healing, and glucose metabolism). The oppositely modulated genes appear related through uncoupling protein 3 (UCP3) that is involved with regulation of fatty acid oxidation and serves to balance glucose and lipid metabolism. Overall, these results identify gender specific differences in UVB induced genetic profiles in the skin of females and males and show female and male X. maculatus respond to UVB differently through pathways involved in reactive oxygen species, wound healing, and energy homeostasis.

show abstract

Section: Discussionsupporting

confidence: 90%

Sex-specific molecular genetic response to UVB exposure in Xiphophorus maculatus skin

Boswell

Titus

et al. 2015

Comparative Biochemistry and Physiology Part C: Toxicology &

View full text Add to dashboard Cite

show abstract

“…Although xeroderma pigmentosum is a rare genetic disease, XPC protein expression is lost in up to 59% of invasive SCCs from non-XPC patients (46), further increasing the relevance of this model to human skin cancer studies. Beyond the persistence of a larger amount of DNA damage after UV exposure in XPC-deficient versus wildtype cells, the subsequent progression to malignancy is not thought to differ between XPC-deficient and wild-type cells.…”

Section: Discussionmentioning

confidence: 99%

Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase

Kawasumi

Lemos

Bradner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc. Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.skin cancer prevention | squamous cell carcinoma | xeroderma pigmentosum M ultiple human epidemiologic studies have revealed that coffee or tea intake decreases the risk of UV-associated nonmelanoma skin cancers (1-4) and non-UV-associated cancers, most prominently hepatocellular and endometrial cancers (5). In the largest study, among 93,676 women, each daily cup of caffeinated coffee consumption was dose-dependently associated with a 5% reduction in the prevalence of nonmelanoma skin cancers, whereas decaffeinated coffee had no effect, and tea had an intermediate effect, consistent with its caffeine content (3). These observations in humans hold true in multiple related studies in mice. Oral intake of caffeine in the drinking water of chronically irradiated SKH-1 hairless mice suppressed UVinduced skin cancer development (6). Topical application of caffeine in UV-pretreated "high-risk" mice also inhibited UVinduced squamous cell carcinomas (SCCs) in hairless mice by 72% (7).UV-induced skin tumor development is a complex, long-term pathological process in vivo, and it is unclear how caffeine sup-

show abstract

“…There are currently conflicting data regarding impairment of XPC function 56,57 . Since up to 59% of invasive SCCs harbor a mutation in XPC as well as p53 54,58,59 , it is straightforward to understand why a drug that blocks proper function of both gene products would lead to an increased risk of NMSC overall, and SCC in particular. Moreover, mTOR inhibition leads to an upregulation of Akt1 with a concomitant downregulation of Akt2 60 .…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Skin cancer in organ transplant recipients: More than the immune system

Wheless

Jacks

Potter

et al. 2014

Journal of the American Academy of Dermatology

View full text Add to dashboard Cite

Organ transplant recipients (OTRs) are at increased risk of developing non-melanoma skin cancers (NMSC). This has long been thought to be due to immunosuppression and viral infection. However, skin cancer risk among individuals with AIDS or iatrogenic immunodeficiency does not approach the levels seen in OTRs, suggesting other factors play a critical role in oncogenesis. In clinical trials of OTRs, switching from calcineurin inhibitors to mammalian Target of Rapamycin (mTOR) inhibitors consistently led to a significant reduction in the risk of developing new skin cancers. New evidence suggests calcineurin inhibitors interfere with p53 signaling and nucleotide excision repair. These two pathways are associated with NMSC, and squamous cell carcinoma (SCC) in particular. This finding may help explain the predominance of SCC over basal cell carcinoma in this population. mTOR inhibitors do not appear to impact these pathways. Immunosuppression, viral infection, and impaired DNA repair and p53 signaling all interact in OTRs to create a phenotype of extreme risk for NMSC.

show abstract

The DNA Damage-Binding Protein XPC Is a Frequent Target for Inactivation in Squamous Cell Carcinomas

Cited by 30 publications

References 30 publications

Sex-specific molecular genetic response to UVB exposure in Xiphophorus maculatus skin

Sex-specific molecular genetic response to UVB exposure in Xiphophorus maculatus skin

Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase

Skin cancer in organ transplant recipients: More than the immune system

Contact Info

Product

Resources

About