Exposure to inorganic arsenic in contaminated drinking water continues to poses an environmental public health threat for hundreds of millions of people worldwide. Arsenic is a human carcinogen. A major target organ of arsenic is the skin. Arsenic-induced skin lesions are an early manifestation of arsenic exposure and toxicity, and are a risk factor for subsequent cancers. However, the mechanism by which arsenic contributes to tumorigenesis remains poorly understood. Recently, we discovered a critical role for FTO (fat mass and obesity-associated protein) as an N6-methyladenosine (m6A) RNA demethylase in arsenic-induced malignant transformation of keratinocytes and tumorigenicity in mice. m6A RNA methylation is the most prevalent modification that occurs in the messenger RNA of most eukaryotes. The objective of this proposal is to determine the mechanism by which FTO as an m6A eraser regulates arsenic-induced skin tumorigenicity. Our preliminary data suggest that FTO, as an m6A eraser, is crucial for arsenic-induced skin tumorigenesis. Thus we hypothesize that FTO, as an m6A eraser, plays a critical role in arsenic tumorigenesis through post- transcriptionally regulating the expression of its essential target genes. To test this hypothesis, we will employ several new methods including transcriptome-wide m6A mapping, eCLIP-seq, and RIP-seq, and a new and clinically relevant model using mice with skin-specific FTO deletion, to determine the role of FTO in arsenic- induced skin tumors. Our hypothesis will be tested in three Specific Aims.
Aim 1 will determine the mechanism by which FTO regulates arsenic-induced tumorigenicity.
Aim 2 will determine the molecular mechanism of FTO up-regulation by arsenic in keratinocytes.
Aim 3 will determine the consequences of FTO inhibition in arsenic- induced tumorigenesis in mice with skin-specific deletion of FTO. Successful completion of the proposed work will provide new mechanistic insights into the molecular basis for arsenic-induced tumorigenesis, linking functional RNA modifications to arsenic tumorigenicity. The resulted findings may also establish FTO and/or its downstream pathways as new druggable targets for preventing and/or treating arsenic-induced skin tumors. Given the association of arsenic and FTO with multiple diseases, our findings will not only be applicable to skin cancers, but may also be relevant to arsenic toxicity in general.
Improving our understanding of the molecular basis for arsenic-induced tumorigenesis is essential for developing better prevention and therapies to reduce the cancer burden caused by arsenic exposure. Our project will not only elucidate the mechanistic roles of FTO and RNA methylation in arsenic-induced skin cancer, the most common cancer caused by arsenic exposure, but also may provide new druggable targets for prevention and therapy of arsenic-induced skin cancer.