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Principal Investigator: Prateek Sharma
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $36,662
Funding agency: National Cancer Institute
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.
Terms: <Acceleration><Acetates><Acetyl CoA><Acetyl Coenzyme A><Acid-Thiol Ligases><Acyl CoA><Acyl CoA Synthetases><Acyl Coenzyme A><Acyl Coenzyme A Synthetases><Affect><Basal Transcription Factor><Basal transcription factor genes><Behavior><Binding Proteins><Body Tissues><Butyrates><CRC prevention><Cancer Cause><Cancer Etiology><Cancer Induction><Cancer Patient><Cancers><Carbohydrates><Catabolism><Cell Body><Cell Culture Techniques><Cell Differentiation><Cell Differentiation process><Cells><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chemopreventive><Chemopreventive Agent><Co A Ligases><Coenzyme A Ligases><Coenzyme A Synthetases><Colon><Colon Cancer><Colon Carcinoma><Colorectal Adenoma><Colorectal Adenomatous Polyp><Colorectal Cancer><Consumption><Data><Death><Diet><Dietary Component><Dietary Fiber><Dietary Intervention><Differentiated Gene><Distal><Down-Regulation><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Esterification><Expression Signature><Family><Family member><Fatty Acids><Fatty Acyl CoA><Fiber><Fructose><GI cancers><GI malignancies><GI microbiota><GI tract cancers><Gastrointestinal Cancer><Gastrointestinal Tract Cancer><Gastrointestinal microbiota><Gene Action Regulation><Gene Expression><Gene Expression Profile><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Targeting><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Glycolysis><Growth><Histone Acetylation><Histones><Immunoblotting><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Individual><Intermediary Metabolism><Intervention><Intervention Strategies><Investigation><LC/MS><Label><Large Bowel Adenoma><Large Bowel Adenomatous Polyp><Large Intestine Adenoma><Levulose><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Long-Chain Acyl CoA><Malignant Cell><Malignant Gastrointestinal Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant neoplasm of gastrointestinal tract><Measurement><Mediating><Mesenchymal><Meta-Analysis><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modification><Murine><Mus><Neoplasm Metastasis><Nuclear><Nutrient><Nutrition Interventions><Nutritional Interventions><Oncogenesis><Organoids><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Physiology><Position><Positioning Attribute><Predisposition><Propionates><Prospective Studies><Protein Binding><Proteomics><RNA Seq><RNA sequencing><RNAseq><Regulation><Regulatory Element><Response Elements><Risk><Role><S-acetate Coenzyme A><Secondary Neoplasm><Secondary Tumor><Short-Chain Fatty Acids><Site><Staining method><Stains><Sterols><Supplementation><Susceptibility><TCGA><Testing><The Cancer Genome Atlas><Tissue Growth><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Tumor Burden><Tumor Load><Up-Regulation><Upregulation><Volatile Fatty Acids><Western Blotting><Western Immunoblotting><Work><adipogenesis><anti-carcinogenic><anticarcinogenic><bound protein><cancer cell><cancer cell metabolism><cancer in the colon><cancer metabolism><cancer metastasis><cancer progression><cancer risk><carcinogenesis><care for patients><care of patients><caring for patients><cell culture><cell cultures><cellular differentiation><chemoprevention agent><chromatin immunoprecipitation-sequencing><colon cancer cell line><colorectal cancer cell line><colorectal cancer prevention><colorectal cancer risk><combat><combinatorial><diet and cancer><diet intervention><dietary><dietary manipulation><diets><enteric microbial community><enteric microbiota><epigenetic regulation><epigenetically><experiment><experimental research><experimental study><experiments><gastrointestinal malignancies><gastrointestinal microbial flora><gene expression pattern><gene expression signature><gene signatures><genetic signature><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><histone modification><in vivo><in vivo Model><inhibitor><insight><interventional strategy><intestinal flora><intestinal microbiota><intestinal microflora><intestinal tract microflora><intestinal tumorigenesis><lipid biosynthesis><lipogenesis><liquid chromatography mass spectrometry><malignancy><microbial><microbial composition><microbial consortia><microbial flora><microbiota><microflora><mortality><mouse model><multispecies consortia><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><ontogeny><pathway><prevent><prevent colorectal cancer><preventing><protein blotting><response><sex><social role><thiokinase><transcription factor><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><tumor><tumor cell metabolism><tumor cell metastasis><tumor growth><tumor metabolism><tumor progression><tumorigenesis><western diet><western-style diet><western-type diet><whole grain>