# Molecular mechanisms of Nutrient sensing in cancer

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $374,242

## Abstract

PROJECT SUMMARY
Metabolic reprogramming is a hallmark of cancer that supports the rapid proliferation and survival of tumor
cells. While many studies have focused on identifying pathways involved in increased glucose uptake and
metabolism by tumor cells, many cancers (particularly acute leukemias) do not depend on glucose and instead
prefer to metabolize fats to support their survival and growth. Despite the pervasiveness of this phenotype,
molecular mechanisms that regulate fatty acid oxidation (FAO) in cancer remain largely unknown. As pathways
that drive fuel addiction may provide new therapeutic targets or biomarkers for personalized therapy, there is a
critical need to identify pathways that regulate dependency on lipids. We have discovered a new nutrient-
dependent signaling pathway that controls fat oxidation in cancers via a little studied member of the prolyl
hydroxylase domain protein family, PHD3. PHDs are a family of α-ketoglutarate dependent dioxygenases that
hydroxylate substrate proline residues and have been linked to fuel switching in cancer. We find that PHD3
regulates fatty acid metabolism by hydroxylating acetyl-CoA carboxylase (ACC2), a regulator of mitochondrial
FAO. In response to nutrient abundance, PHD3 activates ACC2 to inhibit catabolism of fatty acids. Our
proposal will test the hypothesis that tumors with low PHD3 will have excessive fatty acid oxidation due to
deregulation of ACC2 activity, and that PHD3 levels may provide a new metabolic biomarker to identify tumors
vulnerable to therapies that target fat catabolism. This proposal will examine the mechanism by which PHD3-
mediated hydroxylation results in the specific activation of the ACC2 isoform (Aim 1). We will also examine the
physiological stimulation of PHD3 under high nutrient conditions, and examine its coordination with AMPK
signaling, which represses ACC by phosphorylation (Aim 2). Finally, we will examine the consequences of
PHD3 activity, ACC2 hydroxylation, and FAO in AML survival and growth by examining the effects of PHD3
overexpression and vulnerability of tumors with low PHD3 to fat oxidation inhibitors (Aim 3). Our overarching
goal is to elucidate the elements of PHD3 signaling and to leverage these findings to develop therapeutic
strategies to treat tumors dependent on fat oxidation.

## Key facts

- **NIH application ID:** 10159092
- **Project number:** 5R01CA213062-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** MARCIA HAIGIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,242
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159092

## Citation

> US National Institutes of Health, RePORTER application 10159092, Molecular mechanisms of Nutrient sensing in cancer (5R01CA213062-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10159092. Licensed CC0.

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