Fig. 2

Succinate promotes cancer cell growth by inhibiting 2OGDD and through ligating SUCNR-1. Succinate accumulation due to SDH defect leads to increased cytosolic succinate and secretion of succinate. Cytosolic succinate exerts its effect by inhibiting a large number of 2-oxoglutarate-dependent dioxygenases (2OGDD or α-keto glutarate-dependent enzymes) such as prolyl hydroxylase (PHD) and TET (Ten to Eleven Translocation). Inhibition of PHD results in HIF-1α stabilization while inhibition of TET leads to DNA hypermethylation. Extracellular succinate interacts with succinate receptor-1 (SUCNR-1) which signals via PI-3 K to increase HIF-1α expression