Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

• Main Authors: Devilee Peter, Bayley Jean-Pierre, Cervera Ana M, McCreath Kenneth J
• Format: Article
• Language: English
• Published: BMC 2009-10-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/8/1/89

<p>Abstract</p> <p>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 <it>IGFBP7</it>, which encodes a secreted protein upregulated after loss of <it>SDHB</it>, showed decreased occupancy by H3K27me3 in the absence of <it>SDH</it>. 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.</p>