# Interaction between nuclear epigenetic and metabolic pathways in cancer

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2024 · $926,251

## Abstract

Abstract
Despite
cancer
 impressive strides in conventional small molecule therapeutics and novel cancer immunotherapies,
continues to be a devastating disease. Certain cancers are refractory to available therapies, and
patients' responses show large individual variability. Cancer involves striking dysregulation of epigenetic
pathways, with pharmacological approaches targeting chromatin regulators in the clinic and under
development. There is also profound involvement of metabolic pathways in cancer, including fascinating
nuclear-localized metabolic enzymes. These paradigm-shifting pathways represent an entirely new avenue for
targeted therapies, with the potential to directly and specifically modulate cancer-related gene expression
programs. However, our understanding of epigenetic mechanisms in cancer, especially as they connect
to nuclear metabolic pathways, remains in its infancy. Our history of groundbreaking research revealing
new chromatin biology and uncovering genomics and proteomics of the transcription factor p53, both in its role
as a crucial tumor suppressor and as a ruinous oncogene, underpins our proposed novel directions. In
addition, we have new findings of a chromatin-localized role of a cancer-linked metabolic enzyme directly
“fueling” a histone modifying enzyme. Utilizing this background, in this revised proposal, we propose to
investigate novel epigenetic regulation and its intersection with nuclear metabolism, using a variety of normal
and cancer cell lines, as well as translational mouse models of cancer. We will investigate pivotal
developmental- and disease-relevant DNA regulatory elements, called enhancers, which our published findings
expose as crucial in p53 function, but which remain understudied in both wildtype and mutant p53 function. In
addition, we have recently illuminated a
with
will
speckles
chromatin,
expression.
enzyme
wholly novel and unanticipated mechanism of wildtype p53 associating
 membrane-less bodies, called nuclear speckles, to traffic p53's gene targets for enhanced expression; we
dive deeply into the underlying mechanisms for wildtype and oncogenic p53, and explore alterations of
in cancer. Other recent findings implicate a nuclear metabolic-epigenetic axis to coordinate, directly at
 metabolic enzyme production of cofactors with chromatin enzyme function to activate gene
We will unravel mechanisms underlying this organization, identify new examples of metabolic
coordination with epigenetic enzymes, and determinewhether the nuclear metabolic-epigenetic axis is
critical to cancer. Crucially, we have developed an inhibitor targeting ACSS2, a nuclear metabolic enzyme,
which presages potential new advancement in therapy. Taken together, our combined focus on roles and
interactions of epigenetics and metabolism related to cancer promises to delineate novel mechanisms
involved in tumor formation. This paradigm-shifting, multidisciplinary work will bridge separate but
related areas of cancer biology and ...

## Key facts

- **NIH application ID:** 10888233
- **Project number:** 5R35CA263922-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** SHELLEY L BERGER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $926,251
- **Award type:** 5
- **Project period:** 2022-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888233

## Citation

> US National Institutes of Health, RePORTER application 10888233, Interaction between nuclear epigenetic and metabolic pathways in cancer (5R35CA263922-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10888233. Licensed CC0.

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