Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells.
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.
Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. acervera@cnic.es
Ana M
AM
Cervera
Jean-Pierre
JP
Bayley
Peter
P
Devilee
Kenneth J
KJ
McCreath
D000818:Animals; D002345:Carotid Body Tumor / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008745:Methylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D013194:Staining and Labeling; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology
D006657:Histones; D013804:Thenoyltrifluoroacetone; D013385:Succinate Dehydrogenase