Friday, May 10, 2024
5/10/2024
PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a leading cause of cancer mortality and is significantly affected by multifactorial influences including host genetic and epigenetic factors, diet, and microbial composition. One of the most intriguing interventions for mitigating cancer risk and progression is modifying dietary behavior, a powerful approach that has been increasingly investigated. While many studies focus on individual dietary components, it is unclear how distinct metabolic inputs from the dietary milieu integrate to influence cancer progression. Two major nutrients that have been extensively linked to CRC are fructose and fiber. Fructose is highly enriched in Western diets and promotes intestinal tumorigenesis by accelerating de novo lipogenesis (DNL) and glycolysis. Fiber is metabolized by the gut microbiota to produce short-chain fatty acids (SCFAs), which exert anticarcinogenic activity. Fructose and acetate, the most abundant SCFA, converge at a common downstream metabolite, acetyl-CoA, which can be used for DNL or histone modification, making it a central metabolite critical to metabolism and epigenetic regulation. This makes fructose and acetate prime candidates for evaluating crosstalk between multiple dietary inputs in CRC. ACSS2 is the enzyme responsible for converting acetate to acetyl-CoA and is a gene target of several transcription factors which are activated in response to fructose consumption. Thus, ACSS2 is important due to its position at the nexus of catabolic and anabolic metabolism. A key focus of this proposal is on the metabolic and epigenetic effects of dietary fiber and fructose and the role of ACSS2 in mediating these effects. My preliminary data suggest that loss of ACSS2 expression is associated with greater CRC tumor grade and progression. This is potentially due to the downregulation of cell differentiation genes and upregulation of genes relevant to CRC tumor metastasis, such as epithelial-mesenchymal transition. Using a mouse model, we found that manipulating dietary fiber and fructose led to changes to host metabolism in opposing directions, highlighting the need for understanding the integrated effects of these particular nutrients in the cancer context. I hypothesize that fructose manipulates acetyl-CoA pool utilization to prioritize biosynthetic pathways that are advantageous for tumor growth and that acetate exerts epigenetic effects on colonic differentiation gene targets, which are mediated by ACSS2-directed histone acetylation. Aim 1 will determine how acetate and fructose interact to affect CRC growth and acetyl-CoA metabolism through in vitro organoid and cell culture models and in vivo genetic mouse models. Aim 2 will identify the mechanism by which acetate, fructose, and ACSS2 regulate CRC epigenetic modifications and differentiation status through histone proteomics, RNA sequencing, and chromatin immunoprecipitation sequencing. This project will provide novel insights into the combinatorial effects of fiber and fructose and the influence of host gene-diet interactions on susceptibility to dietary impacts on CRC. Our work has significant implications for dietary interventions that can profoundly impact cancer patient care.
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