The Chemistry & Biochemistry Colloquium guest speaker will be Prof. Masaoki Kawasumi: UV-Induced DNA Damage Response, Epigenetic Abnormalities, and Skin Cancer. Dr. Kawasumi is an Assistant Professor in the Department of Dermatology, University of Washington.

Skin cancer is the most prevalent cancer in the United States and is strongly associated with ultraviolet (UV) radiation that generates many mutations. It is critical to avoid excessive sunlight in order to prevent skin cancer. Also, chemoprevention is of great interest. Human epidemiological studies and our mouse studies showed that caffeine prevents UV-induced skin carcinogenesis. We found that the most relevant target of caffeine for skin cancer prevention is the ATR kinase, which senses UV-induced DNA lesions and stops the cell cycle. Genetic inhibition of ATR augmented UV-induced apoptosis and suppressed UV-induced skin cancer development.

Skin cancer has not only genetic mutations but also epigenetic abnormalities which may affect gene expression levels. Our mouse study showed that topical application of caffeine to mouse back skin reduced the frequency of Cdkn2a/p16 promoter mutations. These mutations inhibited the binding of ETS transcription factors, likely reducing the expression of the p16 tumor suppressor. Furthermore, our sequencing analyses of skin cancer identified the gene whose expression is downregulated and whose promoter is methylated, potentially contributing to aggressiveness of skin cancer.

We have been developing CRISPR-Cas9-based epigenome editing tools to change DNA/histone modifications specifically at a genomic region of interest. We targeted the p16 promoter that is methylated in skin cancer, thereby silencing p16. By using our epigenome editing tools, we were able to reactive p16 and inhibit cell proliferation. These epigenome editing tools have many possibilities to regulate the expression of cancer-related genes in order to inhibit cancer phenotypes.