Our overall goal is to understand how mechanisms impacting the epigenetic regulation of gene expression contribute to cancer development and progression. As an initial effort, we have focused on the development of small molecules tools able to profile and perturb the activity of lysine acetyltransferases (KATs). These enzymes catalyze lysine acetylation, a widespread protein posttranslational modification involved in the regulation of gene expression, DNA repair, protein stability, and metabolism. To better understand the role of protein acetylation in cancer, we have taken a multi-pronged approach. 1. Characterization of novel KATs. First, we have developed a chemoproteomic method capable of globally profiling cellular KAT activities. Our initial studies lead to the identification of NAT10, an orphan acetyltransferase that is prevalent in cancer cell lines. Currently we are working with collaborators to characterize the biological activity of NAT10, and its role in cancer cell growth and proliferation. 2. Identification of KAT inhibitors. Targeting the cellular acetylation machinery for anticancer treatment is an emerging therapeutic paradigm; however, KATs represent a relatively unexplored target relative to HDAC and bromodomains. We have developed a new microfluidic assay for the analysis of KAT activity. Currently we are working together with colleagues at the National Center for Advanced Translational Science (NCATS) to apply these assays to identify novel KAT inhibitors. Pilot studies have identified KAT inhibiting chemotypes. As part of this work, we have also applied this platform to characterize pan-assay interference chemotypes, which manifest as hits in screens but are unlikely to act as highly specific KAT inhibitors in cells, and understand the ability of known drugs such as salicylate to modulate KAT activity. 3. Metabolic regulation of epigenetics. We have applied our chemoproteomic KAT probes to identify palmitoyl-CoA as a novel endogenous inhibitor of KAT activity. Palmitoyl-CoA is the most potent endogenous KAT inhibitor reported to date, and our initial biological studies suggest palmitoyl-CoA may mediate context-dependent metabolic interactions between fatty acid metabolism and epigenetic signaling. Future studies are aimed at elucidating this interaction, applying this knowledge to the discovery of novel drug synergies, and developing chemoproteomic approaches capable of providing further insights into metabolic regulation of epigenetic signaling. 4. Diagnostic detection of oncometabolites. Finally, in a collaborative effort we fluorogenic metabolite detection reaction to study of cancers exhibiting epigenetic dysregulation due to metabolic mutations.By focusing on technologies applicable to the study of these enzyme activities directly in living cells, our studies represent foundational steps towards the identification of novel mechanisms of epigenetic regulation, as well as the development of next-generation therapeutics and diagnostics for cancer treatment.
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| Shrimp, Jonathan H; Garlick, Julie M; Tezil, Tugsan et al. (2018) Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes. Mol Pharm 15:729-736 |
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| Kulkarni, Rhushikesh A; Worth, Andrew J; Zengeya, Thomas T et al. (2017) Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling. Cell Chem Biol 24:231-242 |
| Carrer, Alessandro; Parris, Joshua L D; Trefely, Sophie et al. (2017) Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels. J Biol Chem 292:3312-3322 |
| Sinclair, Wilson R; Arango, Daniel; Shrimp, Jonathan H et al. (2017) Profiling Cytidine Acetylation with Specific Affinity and Reactivity. ACS Chem Biol 12:2922-2926 |
| Dahlin, Jayme L; Nelson, Kathryn M; Strasser, Jessica M et al. (2017) Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors. Nat Commun 8:1527 |
| Montgomery, David C; Garlick, Julie M; Kulkarni, Rhushikesh A et al. (2016) Global Profiling of Acetyltransferase Feedback Regulation. J Am Chem Soc 138:6388-91 |
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