Defining the epigenetic signaling pathways regulated by cancer metabolism

Authors

• DC Montgomery
• JM Garlick
• RA Kulkarni
• H Wu
• M Vedadi
• JL Meier

Abstract

There is substantial evidence that chromatin modifiers are sensitive to changes in the cellular concentration of metabolites and cofactors, potentially linking metabolism and gene expression. However, the specific enzymes and metabolites involved in this process are not well characterized, and their direct identification is critical to our basic understanding of how metabolism regulates epigenetic signaling. Here we report a strategy to directly define the metabolic regulation of lysine acetyltransferases (KATs), a major class of chromatin modifiers responsible for protein acetylation. We have developed a powerful chemoproteomic platform using inhibitor-functionalized capture resins to enrich KATs in an active site-dependent manner from their endogenous contexts. This approach has been applied to globally profile the interactions of KAT enzymes with feedback inhibitor CoA, providing new insights into the specific enzymes that are sensitive to metabolic input. By defining the molecular links connecting metabolism and gene expression, these approaches have the potential to illuminate our understanding of cancer biology, and inspire new therapeutic strategies to combat cancer.

Scientific Focus Area: Chemical Biology

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