Fig. 2: FH loss-associated oncogenic signalling.

Upon FH loss, and consequently fumarate accumulation, several oncogenic pathways are altered. For example, fumarate can inhibit the activity of α-ketoglutarate-dependent dioxygenases (αKGDDs), including prolyl hydroxylases (PHDs), Jumonji C-domain lysine demethylases (JmjC-KDMs), and 10–11 translocation (TET) DNA cytosine-oxidizing enzymes. The inhibition of PHDs lead to the stabilization of hypoxia-inducible factor (HIF1A) even in normoxic conditions, known as pseudohypoxia. This phenomenon leads to the activation of signalling cascades associated with tumorigeneses, such as angiogenesis (VEGF), proliferation (TGFα) and glycolytic flux activation (activation of LDHA and GLUT1, inhibition of PDH). In the nucleus, fumarate inhibits the function of JmjC-KDMs and TETs affecting DNA and histones demethylation respectively. Specifically, the inhibition and demethylation of miR200 and CDKN2A (p16) has been shown to trigger an epithelial-to-mesenchymal transition and to inhibit senescence respectively in HLRCC patients. In line with this, FH modulates chromatin accessibility and the activation of FOXA2-mediated antioxidant response. Beyond αKGDDs inhibition, FH loss modulates the energy sensing in the cells. For example, it has been shown to inhibit and activate AMPK function. The inhibition of AMPK can lead to the activation of lipid biosynthesis through acetyl-CoA carboxylase (ACC) and the activation of mTOR signalling. AMPK activation, instead, was shown to protect cells from apoptosis. Further evidence supports the activation of mTOR through the inactivation of ABL1, modulated by the protein-tyrosine phosphatase PTPN12. Additionally, cyclic AMP (cAMP) levels increase upon FH loss, affecting cellular energy metabolism. Beyond energy sensing, well-known oncogenic pathways have been shown to be altered in FH-deficient models. For instance, the tumour suppressor PTEN can be inhibited by fumarate through succination (2SC), activating the phosphatidylinositol-3-kinase (PI3K) cascade. Moreover, FH loss has been associated with the activation of the integrated stress response (ISR) through ATF4. Given the regulation of PI3K pathway, mTOR and ATF4 by FH loss, it is tempting to speculate a potential regulation node between them (red line). In addition, HIRA loss has been recently found to increase the tumorigenic potential of FH-deficient cells through the MYC proto-oncogene and E2F transcriptional programs. Furthermore, FH loss can also regulate and increase DNA damage response and repair upon ionising radiation (IR). Finally, it has been recently discovered that FH loss can trigger the activation of the innate immune response activating the cGAS/STING/TBK1 pathway upon mitochondrial DNA (mtDNA) release to the cytosol. CDKN2A Cyclin-Dependent Kinase Inhibitor 2A, LDHA Lactate Dehydrogenase A, GLUT1 Glucose Transporter 1, PHD Pyruvate Dehydrogenase Complex, VEGF Vascular Endothelial Factor, TGFα Transforming Growth Factor alpha, FOXA2 Forkhead Box A2, AMPK AMP-activated Protein Kinase, PTEN Phosphatase and tensin homolog, ATF4 Activating Transcription Factor 4, mTOR mammalian target of rapamycin, cGAS cyclic GMP–AMP synthase, STING Stimulator Of Interferon Response CGAMP Interactor 1, TBK1 TANK-binding kinase 1, OX Oxidation.