Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

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

doi:10.1186/1476-4598-8-89

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.

Highlights

Forming part of complex II of the respiratory chain, succinate dehydrogenase (SDH) is situated at the intersection of the tricarboxylic acid (Krebs) cycle and oxidative phosphorylation
SDH genes have been considered as tumour suppressors since germ line inactivating mutations in the SDHB, C and D subunit genes can predispose individuals to hereditary paraganglioma (HPGL) [1,2] and phaeochromocytoma [3]
HPGL tumours can be found in the carotid body, a chemoreceptor organ consisting of several cell types [4]

Summary

Introduction

Forming part of complex II of the respiratory chain, succinate dehydrogenase (SDH) is situated at the intersection of the tricarboxylic acid (Krebs) cycle and oxidative phosphorylation. We recently showed that HIF-1 stabilization occurs after chronic silencing of the SDHB gene in cultured cells [9], and previous studies have demonstrated that increased cellular succinate, following SDHD silencing, inhibits the activity of 2-oxoglutarate-dependent prolyl hydroxylases, master regulators of HIF-1 [10].

Results

Conclusion