Role of APOBEC3B in Epigenetic Regulation and Transformation in Cancer Summary Cancer cells generally differ from their normal counterparts by alterations in the sequence of important genes, which change their expression, function and drive the disease. However, over the past few years, research has shown that tumors have other characteristics in which they are distinct from normal tissue, which can modify the expression and function of genes without the genes themselves having mutations in the DNA sequence. These non-mutagenic differences are known as ?epigenetic? changes. A large number of cancer therapies currently in development are designed to target cancerous epigenetic changes in order to revert the tumors to a normal profile. It is of utmost importance to understand how these epigenetic changes are initiated and what pathways are involved in establishing and maintaining the changes in the cancer cells. One potential modifier of the cancer epigenetic landscape is the DNA deaminase APOBEC3B. This enzyme is expressed and active in a large number of cancers, including breast, lung, hematological, bladder, and head & neck. APOBEC3B has been biochemically shown to be capable of epigenetic modifications in the form of RNA- editing and DNA demethylation. However, these epigenetic activities have not yet been investigated in the context of a live cell or animal. In my postdoctoral work, I will closely examine the role of APOBEC3B in changing epigenetic profiles in cancer. This will be explored in cancer cell lines representing a number of different cancer types, including breast, bladder, and hematological malignancies. APOBEC3B's role in a developing tumor will be tested in mice predisposed to develop cancer. Altogether, my studies will advance our understanding of cancer by elucidating a new mechanism of epigenetic regulation. This experimental approach may also reveal a potential therapeutic target for fighting tumors by inhibiting the epigenetic changes brought about by APOBEC3B.
Cancer is the second leading cause of death in the USA and is a worldwide epidemic. Cancer cells differ from their normal counterparts by genetic mutations, as well as by epigenetic changes, with many of the new cancer therapies in development targeting the changes in the epigenome. In this project, I will investigate how APOBEC3B, a protein overexpressed in a broad range of cancer types, modulates the epigenome in cancer, which has the potential to lead to targeted epigenetic therapies for APOBEC3B positive tumors.
