Paragangliomas and pheochromocytoma (PPGLs) are hereditary tumors in about 40% of cases. Mutations in the genes encoding for components of the mitochondrial succinate dehydrogenase protein complex (SDHB, SDHD, SDHC) are among the most prevalent. Most PPGLs have a benign behavior, but patients with germline SDHB mutations may develop metastatic PPGLs in up to 30% of cases. This suggest that the SDH substrate, succinate, is key for the activation of the metastatic cascade. The last decade has witnessed significant advances in our understanding of how succinate may have oncogenic properties. It is now widely accepted that succinate is an oncometabolite that modifies the epigenetic landscape of SDH-deficient tumors via modulating the activities of DNA and histone modification enzymes. In this chapter, we summarize recent discoveries linking SDH-deficiency and metastasis in SDH-deficient PPGLs via inhibition of DNA methylcytosine dioxygenases, histone demethylases and modified expression of non-coding RNAs. We also highlight promising therapeutic avenues that may be used to counteract epigenetic deregulations.
Part of the book: Pheochromocytoma, Paraganglioma and Neuroblastoma