Abstract
Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes and tumor suppressors. Loss-of-function mutations give rise to hereditary paragangliomas/pheochromocytomas and hereditary leiomyomatosis and renal cell carcinoma. Inactivation of SDH and FH results in an abnormal accumulation of their substrates succinate and fumarate, leading to inhibition of numerous α-ketoglutarate dependent dioxygenases, including histone demethylases and the ten-eleven-translocation (TET) family of 5-methylcytosine (5 mC) hydroxylases. To evaluate the distribution of DNA and histone methylation, we used immunohistochemistry to analyze the expression of 5 mC, 5-hydroxymethylcytosine (5 hmC), TET1, H3K4me3, H3K9me3, and H3K27me3 on tissue microarrays containing paragangliomas/pheochromocytomas (n = 134) and hereditary and sporadic smooth muscle tumors (n = 56) in comparison to their normal counterparts. Our results demonstrate distinct loss of 5 hmC in tumor cells in SDH- and FH-deficient tumors. Loss of 5 hmC in SDH-deficient tumors was associated with nuclear exclusion of TET1, a known regulator of 5 hmC levels. Moreover, increased methylation of H3K9me3 occurred predominantly in the chief cell component of SDH mutant tumors, while no changes were seen in H3K4me3 and H3K27me3, data supported by in vitro knockdown of SDH genes. We also show for the first time that FH-deficient smooth muscle tumors exhibit increased H3K9me3 methylation compared to wildtype tumors. Our findings reveal broadly similar patterns of epigenetic deregulation in both FH- and SDH-deficient tumors, suggesting that defects in genes of the TCA cycle result in common mechanisms of inhibition of histone and DNA demethylases.
Highlights
The tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH) and fumarate hydratase (FH) are mutated in a subset of human cancers, leading to alterations in cell metabolism
Since TET1 is responsible for the oxidation of 5mC to 5hmC and gliomas with loss of 5hmC expression have been reported to show nuclear exclusion of TET1 expression [28], we investigated this correlation in SDH and FH mutant tumors
Loss-of-function mutations in SDH and FH leading to the accumulation of succinate and fumarate indirectly act as inhibitors of α-KG dependent dioxygenases
Summary
The tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH) and fumarate hydratase (FH) are mutated in a subset of human cancers, leading to alterations in cell metabolism. Germline mutations in SDHA [1], SDHB [2], SDHC [3], SDHD [4], and SDHAF2 [5] cause paraganglioma/pheochromocytoma (PGL/PCC). Inactivating germline mutations of FH result in hereditary leiomyomatosis and renal cell carcinoma (HLRCC), which is inherited in an autosomal dominant manner [7, 8]. Leiomyomas, benign smooth muscle tumors predominantly found in the skin and uterus, are the most common tumor type in HLRCC, but papillary type 2 renal cell carcinomas may occur, less frequently. Rare germline mutations in FH were recently reported in patients with PGL/PCC [9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
