Hypoxic Regulation of Glutamine Metabolism through HIF1 and SIAH2 Supports Lipid Synthesis that Is Necessary for Tumor Growth

Recent reports have identified a phenomenon by which hypoxia shifts glutamine metabolism from oxidation to reductive carboxylation. We now identify the mechanism by which HIF-1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex a ketoglutarate dehydrogenase (alpha KGDH). HIF-1 activation promotes SIAH2 targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the alpha KGDH complex (OGDH2). Knockdown of SIAH2 or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in alpha KGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis. 336KA OGDH2-expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immunodeficient mice. Reversal of hypoxic mitochondrial function may provide a target for the development of next-generation anticancer agents targeting tumor metabolism.