# Understanding succinate-induced global transcriptional and epigenetic reprogramming and identifying unique vulnerabilities intrinsic to SDH-deficient cells

> **NIH NIH F30** · MAYO CLINIC ROCHESTER · 2020 · $47,777

## Abstract

Project Summary
Our laboratory is interested in studying how broken tricarboxylic acid (TCA) cycle metabolism
can cause cancer. Specifically, we study familial paraganglioma (PGL), a neuroendocrine
cancer that is a model for tumorigenesis driven by metabolic derangement. Familial PGL
displays an apparent autosomal dominant inheritance pattern resulting from loss of both copies
of genes encoding subunits of succinate dehydrogenase (SDH), a TCA cycle enzyme that
catalyzes the conversion of succinate to fumarate. The current working model for PGL
tumorigenesis involves bi-allelic SDH loss with subsequent accumulation of succinate, which
competitively inhibits the activities of several dioxygenase enzymes that demethylate histones
and DNA, and suppress hypoxic signaling. This model is supported by observations in human
PGL tumors that SDH loss is accompanied by global hypermethylation of histones and DNA,
and the constitutive activation of hypoxic signaling. To date, however, there is no clear
mechanistic explanation for how succinate-induced activation of hypoxic signaling and
global methylation of histones and DNA drives PGL tumorigenesis. Additionally, there is
no explanation for why SDH loss has a predilection to specifically cause neuroendocrine
tumors. A long-term goal of this proposal is to understand how succinate accumulation
promotes tumorigenesis by rewriting the epigenome and altering patterns of gene expression.
Our central hypothesis is that understanding cellular responses to succinate accumulation will
identify and validate biological targets driving tumorigenesis and susceptible to therapeutic
intervention in PGL. Recent work from our laboratory has revealed that the hypoxic and
epigenetic effects of succinate accumulation are modulated by oxygen availability. In this
project, we seek to understand how succinate accumulation and low oxygen synergize to drive
PGL tumorigenesis, and then to identify vulnerabilities intrinsic to SDH-deficient cells. Aim 1 will
characterize the transcriptome- and epigenome-wide effects of succinate accumulation in cell
culture models or SDH loss. Aim 2 will characterize the tissue-specific transcriptome-wide
effects of SDH loss in various mouse tissues. Finally, Aim 3 will identify gene products whose
loss is synthetically lethal to SDHC-deficient cells.

## Key facts

- **NIH application ID:** 9966917
- **Project number:** 5F30CA220660-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** John Andrew Smestad
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,777
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-05-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966917

## Citation

> US National Institutes of Health, RePORTER application 9966917, Understanding succinate-induced global transcriptional and epigenetic reprogramming and identifying unique vulnerabilities intrinsic to SDH-deficient cells (5F30CA220660-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9966917. Licensed CC0.

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