C/EBP? expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBP? confers susceptibility to UVB-induced skin squamous cell carcinomas.

ABSTRACT: Human epidermis is routinely subjected to DNA damage induced by UVB solar radiation. Cell culture studies have revealed an unexpected role for C/EBP? (CCAAT/enhancer-binding protein-?) in the DNA damage response network, where C/EBP? is induced following UVB DNA damage, regulates the G(1) checkpoint, and diminished or ablated expression of C/EBP? results in G(1) checkpoint failure. In the current study we observed that C/EBP? is induced in normal human epidermal keratinocytes and in the epidermis of human subjects exposed to UVB radiation. The analysis of human skin precancerous and cancerous lesions (47 cases) for C/EBP? expression was conducted. Actinic keratoses, a precancerous benign skin growth and precursor to squamous cell carcinoma (SCC), expressed levels of C/EBP? similar to normal epidermis. Strikingly, all invasive SCCs no longer expressed detectable levels of C/EBP?. To determine the significance of C/EBP? in UVB-induced skin cancer, SKH-1 mice lacking epidermal C/EBP? (CKO?) were exposed to UVB. CKO? mice were highly susceptible to UVB-induced SCCs and exhibited accelerated tumor progression. CKO? mice displayed keratinocyte cell cycle checkpoint failure in vivo in response to UVB that was characterized by abnormal entry of keratinocytes into S phase. Our results demonstrate that C/EBP? is silenced in human SCC and loss of C/EBP? confers susceptibility to UVB-induced skin SCCs involving defective cell cycle arrest in response to UVB.

SUBMITTER: Thompson EA 

PROVIDER: S-EPMC3418815 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature