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-1α (HIF1α) can suppress tumor cell proliferation. Here, we discovered that HIF1α 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, HIF1α 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 HIF1α-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 HIF1α acts as a tumor suppressor, highlighting the in vivo relevance of these findings. In conclusion, we show that HIF1α inhibits cytosolic and mitochondrial aspartate biosynthesis and that this mechanism is the molecular basis for HIF1α tumor suppressor activity. Meléndez-Rodríguez et al. show that HIF1α impairs oxidative and reductive aspartate biogenesis, which consequently drives HIF1α-dependent suppression of tumor cell proliferation. Mechanistically, HIF1α represses the aspartate-producing enzymes GOT1 and GOT2 in several biological settings, including human VHL-deficient renal cell carcinoma, in which HIF1α can act as a tumor suppressorThis work was supported by grants from Ministerio de Economía y Competitividad (SAF2016-76815 and SAF2017-90794-REDT) and Fundació La Marató de TV3 (534/C/2016). F.M.-R. is supported by Ministerio de Economía y Competitividad (BES-2014-068618). A.A.U is supported by the CAM “Atracción de Talento” program. D.L. is supported by the VIB-Marie Curie omics program. S.-M.F. acknowledges funding support from a Marie Curie CIG, FWO Odysseus II, FWO Research Grants, Eugène Yourassowsky Schenking, and KU Leuven Methusalem co-funding. O.R. has a contract for accessing the Spanish System of Science, Technology and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM). R.S.P acknowledges funding support from Ministerio de Educación y Ciencia (SAF2015-64215-R) and Fundacion Leticia Castillejo Castillo. A.M.-R. acknowledges funding support from Ministerio de Economía y Competitividad (PI15/00107)