My overarching goal is to identify new pathways that can be targeted to prevent or treat human malignancies. I believe that innovation in cancer care will be driven by the design of therapies to disrupt crucial processes that cancers use to grow, adapt, and resist therapies. I am focused on the crosstalk between epigenetic and metabolic regulation as these two fields are ripe for exploitation, but recent findings have yet to lead to widespread adoption of principles to safely and effectively target these pathways. Both metabolic and epigenetic pathways are in continuous flux as organisms and their cells respond to environme...

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My overarching goal is to identify new pathways that can be targeted to prevent or treat human malignancies. I believe that innovation in cancer care will be driven by the design of therapies to disrupt crucial processes that cancers use to grow, adapt, and resist therapies. I am focused on the crosstalk between epigenetic and metabolic regulation as these two fields are ripe for exploitation, but recent findings have yet to lead to widespread adoption of principles to safely and effectively target these pathways. Both metabolic and epigenetic pathways are in continuous flux as organisms and their cells respond to environmental conditions by altering gene expression and metabolic activity. Therefore, these processes must be coordinated in fundamental and essential ways.

My prior work established one such coordinated regulation based on the enzymatic activity of histone acetyltransferase 1 (HAT1). This enzyme responds to high levels of the core metabolite acetyl-Co-A by inducing transcription of core histones, especially histone H4, a fundamental unit of the nucleosome. Therefore, HAT1 links metabolite ability with the construction of new chromatin. My data suggests that HAT1 represents an important dependency in multiple human tumors.

This proposal seeks to establish further mechanistic details of the HAT1 enzymatic pathway with the goal of identifying principles to harness this pathway for anti-cancer therapy.

First, I will determine how HAT1 binding to the genome causes new histone H4 to be synthesized in response to acetyl-Co-A.

Second, I will characterize the molecular basis of how HAT1 is activated by growth pathways and altered in human tumors.

Completion of these aims should provide a platform to support my long-term goal of designing small-molecule HAT1 complex inhibitors to treat human tumors.

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