# Role of acetyl-CoA in linking cancer cell metabolism and epigenetics

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $397,600

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, due largely to the fact that it
metastasizes early and is typically detected late, when tumors can no longer be resected. Obesity increases
an individual’s risk of developing PDA, although the mechanisms driving this link are poorly understood. This
proposal investigates the hypothesis that insulin signaling in PDA cells promotes metabolic alterations and
changes in gene expression that facilitate tumor development and progression, potentially pointing towards
new strategies to prevent PDA in at-risk populations or to improve PDA treatment outcomes.
Histone acetylation is highly sensitive to the availability of the acetyl donor acetyl-CoA, and our previous work
has defined a role for the metabolic enzyme ATP-citrate lyase (ACLY) in the regulation of histone acetylation
levels in diverse mammalian cell types. Histone acetylation plays key roles in PDA tumorigenesis, although
the mechanisms that drive altered histone acetylation are not well understood. In preliminary studies, we have
found that insulin and insulin-like growth factor (IGF) stimulation of PDA cells results in ACLY Ser455
phosphorylation, increasing its activity, as well as elevated levels of global histone acetylation. ACLY is
phosphorylated downstream of AKT, and AKT inhibition suppresses histone acetylation globally and at cancer-
relevant loci. We hypothesize that elevated insulin/IGF levels promote metabolic and transcriptional
remodeling in PDA cells, promoting tumor progression. To test this, we will define the role of insulin/IGF
signaling in metabolic and epigenetic remodeling in KRAS mutant PDA cells, using a combination of
hypothesis-driven and unbiased approaches. Finally, we will test the role of ACLY in mediating obesity-linked
pancreatic tumorigenesis, as well as the potential to target acetyl-CoA-dependent processes to suppress tumor
growth and improve therapeutic responses. This study will elucidate new mechanisms through which systemic
metabolism influences cellular metabolism and the tumor epigenome. Findings from this study have potential
to provide a mechanistic rationale for nutritional recommendations for PDA patients and/or to identify new
therapeutic targets to prevent tumor recurrence after surgical resection or to use in conjunction with
chemotherapy to improve its efficacy.

## Key facts

- **NIH application ID:** 9973530
- **Project number:** 2R01CA174761-06A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kathryn Elaine Wellen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,600
- **Award type:** 2
- **Project period:** 2014-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973530

## Citation

> US National Institutes of Health, RePORTER application 9973530, Role of acetyl-CoA in linking cancer cell metabolism and epigenetics (2R01CA174761-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973530. Licensed CC0.

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