Cancer is a disease that arises from genomic alterations in somatic cells and it is the accumulation of genetic alterations that drives tumorigenesis. Moreover, it is the rate at which a developing tumor cell acquires these genetic alterations that ultimately determines the onset of cancer. Human skin is routinely subjected to DNA damage induced by solar radiation and keratinocytes have developed intricate pathways to response to UVB-induced DNA damage. Recently, we provided the first genetic evidence CCAAT/enhancer binding protein 1 (C/EBP1), a member of the basic leucine zipper family of transcription factors, functions as an epithelial tumor suppressor through utilization of mice with an epidermal-targeted ablation of C/EBP1. These mice are highly susceptible to UVB- and carcinogen-induced squamous papilloma development and these benign skin tumors display a highly accelerated rate of malignant progression to squamous cell carcinomas. Human skin squamous cell carcinomas and basal cell carcinomas as well as mouse skin squamous carcinomas display weak or ablated expression of C/EBP1. Together these findings suggest a tumor suppressor function of C/EBP1 in skin cancer through maintenance of the genome. We hypothesize that reduced or ablated expression of C/EBP1 results in an impaired DNA damage-induced G1 checkpoint, resulting in the accumulation of somatic mutations and promoting skin cancer progression. The overall objective of this proposal is to understand how the loss of C/EBP1 contributes to an increased rate of malignant tumor progression focusing on the role of C/EBP1 in the DNA damage- induced G1 checkpoint. To address this objective we aim to 1) delineate the molecular mechanism through which C/EBP1 functions in the DNA damaged-induced G1 checkpoint and 2) provide molecular evidence for increased genome instability/mutator phenotype in response to C/EBP1 ablation. .
Understanding how C/EBP1 influences the rate of cancer progression and the acquisition of mutations will provide further insights to the mechanisms of carcinogen- and UVB-induced skin cancer as well as numerous cancers where C/EBP1 expression is diminished. Recent analysis of the genomes from human cancers discovered that mutations in specific cancer associated genes can vary dramatically within a give tumor type and suggest the identification of the origin of genomic point mutations may be a more effective strategy for cancer treatment than targeting a specific cancer gene as mutations in other essential genes will be enhanced and selected by the mutator phenotype. Drugs that target point mutation genetic instability may delay the accumulation of mutations and subsequently prevent cancer onset.
| Hall, J R; Messenger, Z J; Tam, H W et al. (2015) Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes. Cell Death Dis 6:e1700 |
| Hall, Jonathan R; Bereman, Michael S; Nepomuceno, Angelito I et al. (2014) C/EBP? regulates CRL4(Cdt2)-mediated degradation of p21 in response to UVB-induced DNA damage to control the G1/S checkpoint. Cell Cycle 13:3602-10 |
