Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

Cervera, Ana M; Bayley, Jean-Pierre; Devilee, Peter; McCreath, Kenneth J

doi:10.1186/1476-4598-8-89

Cited by 156Adrenal and Paraganglionic TumorsEpigenetics and DNA MethylationChromatin Remodeling and Cancer

Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

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Cervera, Ana M, Bayley, Jean-Pierre, Devilee, Peter, McCreath, Kenneth J·2009·Molecular Cancer

DOI 10.1186/1476-4598-8-89PMC PMC2770992

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Abstract

Remodelling of mitochondrial metabolism is a hallmark of cancer. Mutations in the genes encoding succinate dehydrogenase (SDH), a key Krebs cycle component, are associated with hereditary predisposition to pheochromocytoma and paraganglioma, through mechanisms which are largely unknown. Recently, the jumonji-domain histone demethylases have emerged as a novel family of 2-oxoglutarate-dependent chromatin modifiers with credible functions in tumourigenesis. Using pharmacological and siRNA methodologies we show that increased methylation of histone H3 is a general consequence of SDH loss-of-function in cultured mammalian cells and can be reversed by overexpression of the JMJD3 histone demethylase. ChIP analysis revealed that the core promoter of IGFBP7 , which encodes a secreted protein upregulated after loss of SDHB , showed decreased occupancy by H3K27me3 in the absence of SDH . Finally, we provide the first evidence that the chief (type I) cell is the major methylated histone-immunoreactive constituent of paraganglioma. These results support the notion that loss of mitochondrial function alters epigenetic processes and might provide a signature methylation mark for paraganglioma.

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Elevated succinate levels can cause epigenetic dysregulation.
“Elevated succinate levels can lead to epigenetic dysregulation (Cervera et al., 2009; Smith et al., 2007).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Cervera et al., 2009
R-2HG, succinate, and fumarate can inhibit multiple 2-oxoglutarate-dependent dioxygenases, including JmjC histone demethylases and TET proteins, at sufficiently high concentrations.
“R-2HG, succinate, and fumarate are all capable of inhibiting multiple 2-oxoglutarate-dependent dioxygenases, including the JmjC histone demethylases and TET proteins, when present at sufficiently high concentrations (Figure 6B) (Cervera et al., 2009; Chowdhury et al., 2011; Figueroa et al., 2010; Koivunen et al., 2012; Lu et al., 2012; Smith et al., 2007; Turcan et al., 2012; Xiao et al., 2012; Xu”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Cervera et al., 2009
Increased levels of succinate and fumarate can inhibit Jumonji C-domain-containing histone demethylases and TET enzymes, driving a widespread hypermethylation phenotype that disrupts normal cell differentiation.
“Like 2HG accumulation, increased levels of succinate and fumarate can inhibit Jumonji C-domain–containing histone demethylases and TET enzymes, driving a widespread hypermethylation phenotype that disrupts normal cell differentiation (179, 180).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [179]

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Authors: Cervera, A. M., Bayley, J.-P., Devilee, P., & McCreath, K. J.
Affiliations: Spanish National Centre for Cardiovascular Research (ES)
Leiden University Medical Center (NL)
Corresponding author: McCreath, Kenneth J
ORCID: Bayley, Jean-Pierre
Devilee, Peter
Venue: Molecular Cancer
Publisher: Springer Science and Business Media LLC
Published: 2009-10-22
Volume: 8
Issue: 1
Pages: 89-89
ISSN: 1476-4598 (ISSN-L)
DOI: 10.1186/1476-4598-8-89
PMC: PMC2770992
OpenAlex: W2166443483
Cited by: 156
References: 24
Citations by year: 2026: 12 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 13 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 9 · 2016: 9 · 2015: 14 · 2014: 18 · 2013: 12 · 2012: 16
FWCI: 8.11
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Molecular Cancer (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: European Commission
Ministerio de Ciencia e Innovación
Centro Nacional de Investigaciones Cardiovasculares
Instituto de Salud Carlos III (PI0600299)
Topics: Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords: succinate dehydrogenase, histone H3 methylation, JMJD3, H3K27me3, IGFBP7, paraganglioma, pheochromocytoma, mitochondrial metabolism, epigenetic dysregulation, chief cells, cancer epigenetics
MeSH terms: Animals, Carotid Body Tumor, Histones, Humans, Immunohistochemistry, Methylation, Protein Processing, Post-Translational, Staining and Labeling, Succinate Dehydrogenase, Thenoyltrifluoroacetone, Gene Silencing, Cell Line, Tumor, Rats

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Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

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