Epigenetic and metabolic reprogramming of SDH-deficient paragangliomas

Abstract

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla or extra-adrenal paraganglia. Around 40% of all cases are caused by a germline mutation in a susceptibility gene, half of which being found in an SDHx gene (SDHA, SDHB, SDHC, SDHD or SDHAF2). They encode the four subunits and assembly factor of succinate dehydrogenase (SDH), a mitochondrial enzyme involved both in the tricarboxylic acid cycle and in the electron transport chain. SDHx mutations lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting iron(II) and alpha-ketoglutarate dependent dioxygenases thereby regulating the cell's hypoxic response and epigenetic processes. Moreover, SDHx mutations induce cell metabolic reprogramming and redox imbalance. Major discoveries in PPGL pathophysiology have been made since the initial discovery of SDHD gene mutations in 2000, improving the understanding of their biology, and patient management. It indeed provides new opportunities for diagnostic tools and innovative therapeutic targets in order to improve the prognosis of patients affected by these rare tumors, in particular in the context of metastatic diseases associated with SDHB mutations. This review first describes an overview of the pathophysiology and then focuses on clinical implications of the epigenetic and metabolic reprogramming of SDH-deficient PPGL.

Whole‐exome sequencing identified novel variants in three Chinese Leigh syndrome pedigrees

“…SDHA not only participates in the OXPHOS pathway, but also has tumor suppressive function. Apart from SDHA, the other SDHx (SDHB, SDHC and SDHD) and SDHAF2 also have tumor suppressor function, though only SDHA, SDHB, SDHD, and SDHAF1 are involved in energy generation (Alston et al, 2012;Bardella et al, 2011;Jackson et al, 2014;Moog et al, 2020). Additionally, Renkema et al have reported that the same SDHA variant presented not only in paragangliomas and pheochromocytomas, but also in LS patients (Renkema et al, 2015).…”

Mitochondrial Tumor Suppressors—The Energetic Enemies of Tumor Progression

“…Some of the therapeutic approaches in SDH-mutated metastatic cancers involve targeting metabolic reprogramming, redox imbalance, pseudohypoxia or epigenetic reprograming. Among these drugs are inhibitors of oxidative phosphorylation, HIF2a and PARP, or demethylating agents that currently are or will soon be tested in clinical trials (203). While the studies of mitochondrial tumor suppressors are still at a relatively early stage, they already provided many valuable insights into biology and dependencies of cancer cells and deepened our appreciation on the important role of mitochondria in tumor progression.…”

Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma

“…There is an urgent need for more transformative therapies in order to improve disease outcomes in patients with SDHB-related PHEO/PGL. Recently, Moog et al suggested angiogenesis, pseudohypoxia, epigenetics, metabolic reprogramming, and redox imbalance as therapeutic target options for the treatment of SDH-deficient PGLs [21].…”