This is an application for a K08 for Dr. Joshua Gruber, an Instructor of Medicine at Stanford University. Dr. Gruber wishes to establish himself as a clinician-scientist at the forefront of metabolite- epigenetics crosstalk with a long-term goal of establishing novel drug targets for patients with early and advanced stage malignancies. This K08 award will provide Dr. Gruber support to achieve the following goals for career development: 1) Determine molecular mechanisms that drive histone acetyltransferase 1 (HAT1)-dependent malignancies; 2) Mechanistically characterize potential HAT1 activators and inhibitors; 3) Identify mechanisms of how dietary fiber-derived propionate modifies chromatin. Dr. Gruber will be mentored by Dr. Michael Snyder, an established expert in mass spectrometry approaches including proteomics and metabolite quantitation. Dr. Gruber will be co-mentored by Dr. Calvin Kuo, an expert in cancer biology and nutrient metabolism. Dr. Gruber has established a mentoring committee including Dr. James Chen, Stanford Professor of Chemical and Systems biology to advise on aspects of chemical biology; Dr. Mark Smith, director of the Medicinal Chemistry Knowledge Center; Dr. Kevin Contrepois, Scientific Director of the Stanford Metabolic Health Center, to provide mass spectrometry training; and Zena Werb, Professor of Anatomy, University of California San Francisco to advise on experimental models of tumorigenesis and breast cancer biology. Cancer cell growth is coupled to nutrient metabolism to ensure adequate nutrients exist to fuel cell division. Molecular metabolite sensors allow for cells to respond to changes in nutrient availability. Acetyl-co-A is a critical metabolite for biosynthetic processes, signaling and epigenetics. However, metabolite sensors of acetate and other acyl-containing metabolites are poorly understood. Therefore, an improved understanding of acetyl-co-A sensing may allow for the development of novel approaches to diagnose, treat or prevent malignancy. Dr. Gruber has identified the histone acetyltransferase HAT1 as a potential sensor of acetyl-co-A and acyl-containing short chain fatty acids. To identify exploitable properties of the HAT1 metabolite-sensing pathway, Dr. Gruber plans a detailed molecular investigation of HAT1-dependency in human tumors to provide an understanding of the properties that make HAT1 a potential anti-cancer drug target (aim 1). To advance the ability to manipulate HAT1 catalytic activity, Dr. Gruber has screened for small molecule chemical activators and inhibitors, which will be biochemically characterized (aim 2). Finally, he plans to define mechanisms by which HAT1 incorporates short-chain fatty acids to chromatin (aim 3). This research will provide scientific foundations and essential career training to lead to an independent academic research position for Dr. Gruber with the expectation of R01-level funding by the conclusion of the K award period.
A better understanding of how metabolite sensing informs epigenetic responses has promise to uncover novel therapeutic targets for a broad spectrum of human malignancies because cancers depend on metabolic processes to fuel cell division and support malignant gene expression programs. This research proposal seeks to understand contributions of acetyl-co-A and short-chain fatty acids to breast cancer biology and characterize chemical inhibitors and activators of these pathways. In particular, focus on the histone acetyltransferase 1 enzyme complex will serve as a platform to better understand how cancer cells import acyl groups for nuclear epigenetic reactions that drive malignant processes.
