# Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $175,088

## Abstract

Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a
particular nutrient source. For example, glucose drives a gene expression program characterized
by activating genes involved in its metabolism, in part, by increasing glucose-derived histone
acetylation. We recently expanded the known metabolites that integrate into epigenetic signaling
and found that medium-chain lipid-derived acetyl-CoA is a major source of carbon for histone
acetylation. This signaling axis leads to activation of stress response genes, including lipid
metabolic genes, and inhibition of cell cycle gene expression. Our preliminary data presented in
this application expand upon these gene expression observations and reveal lipid oxidation
induces potent suppression of the cell cycle, lowers cellular proliferation across a range of cell
lines, and lowers tumor burden in a mouse model of liver cancer. However, a critical gap in our
knowledge remains that prevent us from fully understanding how the role of lipids and their
oxidation in cancer: In which sub-cellular organelle are medium-chain lipids oxidized to generate
acetyl-CoA for histone acetylation? Is the oxidation of MCTs required for their effect on cellular
proliferation? What are the key cellular mediators of these epigenetic signals? There is a critical
need to understand the full range of lipid’s molecular effects in order to enable more intelligent
therapies for cancer. Although it is widely accepted that mitochondria oxidize lipids and are prime
candidate sites of mediating communication between nutrients and the nucleus, no data exist to
support this notion. Therefore, the single objective of this exploratory grant application is to
determine the site(s) and molecular mediators of lipid signaling on epigenetics. Aim 1 will test
three candidate sites of lipid metabolism using a combination of pharmacological and genetic
approaches. In a complementary parallel approach, Aim 2 will perform an unbiased CRISPR-
Cas9 screen to identify genes that are required for the suppressive effects of medium-chain lipids
on cellular proliferation. This project is significant because it will explain the molecular
mechanisms by which lipids and their oxidation mediate the positive effects cellular proliferation
and cancer outcomes. We put forth conceptual and technical innovations that will both follow
directed hypotheses and allow unbiased discovery of the most important aspects of the response
to medium-chain lipids. Successful completion of this project will identify new aspects of inter-
organelle communication in cancer.

## Key facts

- **NIH application ID:** 9938509
- **Project number:** 5R21CA228342-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew D Hirschey
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $175,088
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938509

## Citation

> US National Institutes of Health, RePORTER application 9938509, Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics (5R21CA228342-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938509. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*