Epigenomic Drivers of EBV Epithelial Cancers

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PROJECT 1 – PROJECT SUMMARY The long-term goal of this project is to determine how EBV establishes an oncogenic latent epigenome in EBV- associated epithelial cancers and to leverage this information to develop new therapeutic strategies to target EBV latent infection in epithelial cancers. All EBV cancers share the common feature of maintaining latent viral genomes that express a restricted subset of viral oncogenes. EBV epithelial cancers also have the distinguishing feature of CpG Island Methylation Phenotype (CIMP). The role of EBV latent infection in driving CIMP, and the role of CIMP in regulating oncogenic EBV latency are not fully elucidated, but critical for understanding EBV carcinogenesis. In Aim 1, we propose to investigate how EBV latent infection promotes CIMP. We will test the specific hypothesis that EBNA1-driven episome maintenance induces a PARP1-dependent DNA-damage response that drives CIMP. In collaboration with Project 2, we will investigate the role of PARP1 and UHRF1 in the formation of site-specific viral and host DNA methylation. In collaboration with Project 3, we will explore the role of PI3K activation in controlling replication stress in epithelial cancers. In Aim 2, we will test the hypothesis that CIMP and other somatic changes, such as PI3K and ARID1A mutations, facilitate the formation of a viral type II latency. In collaboration with Project 2, we will examine the role of CTCF and CIMP on EBV 3D conformation. With Project 3, we will investigate how metabolic changes favor establishment of type II latency in epithelial cancers. Finally, we will work in collaboration with Projects 2, 3 and all Cores to identify new therapeutic approaches to treat EBV(+) epithelial cancers. To this end, we have developed new small molecule inhibitors and mouse models of EBV epithelial cancers to better understand these mechanisms and test therapeutic strategies. The overarching hypothesis of Project 1 is that EBV epithelial malignancies depend on the establishment of a distinct epigenetic state involving CpG methylator phenotype (CIMP) and that key regulators of this epigenetic state are therapeutic targets in EBV epithelial carcinogenesis.