Back to Search Start Over

Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

Authors :
Devilee Peter
Bayley Jean-Pierre
Cervera Ana M
McCreath Kenneth J
Source :
Molecular Cancer, Vol 8, Iss 1, p 89 (2009)
Publication Year :
2009
Publisher :
BMC, 2009.

Abstract

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.

Details

Language :
English
ISSN :
14764598
Volume :
8
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Molecular Cancer
Publication Type :
Academic Journal
Accession number :
edsdoj.7163c98ef9b4bccae47ae9874461d4c
Document Type :
article
Full Text :
https://doi.org/10.1186/1476-4598-8-89