HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

Cellular aspartate drives cancer cell proliferation, but signaling pathways that rewire aspartate biosynthesis to control cell growth remain largely unknown. Hypoxia-inducible factor-1 alpha (HIF1 alpha) can suppress tumor cell proliferation. Here, we discovered that HIF1 alpha acts as a direct repressor of aspartate biosynthesis involving the suppression of several key aspartate-producing proteins, including cytosolic glutamic-oxaloacetic transaminase-1 (GOT1) and mitochondrial GOT2. Accordingly, HIF1 alpha suppresses aspartate production from both glutamine oxidation as well as the glutamine reductive pathway. Strikingly, the addition of aspartate to the culture medium is sufficient to relieve HIF1 alpha-dependent repression of tumor cell proliferation. Furthermore, these key aspartate-producing players are specifically repressed in VHL-deficient human renal carcinomas, a paradigmatic tumor type in which HIF1 alpha acts as a tumor suppressor, high-lighting the in vivo relevance of these findings. In conclusion, we show that HIF1 alpha inhibits cytosolic and mitochondrial aspartate biosynthesis and that this mechanism is the molecular basis for HIF1 alpha tumor suppressor activity.