HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis

Cell Reports
Florinda Meléndez-RodríguezJulián Aragonés

Abstract

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.

Citations

Apr 5, 2020·Acta Neuropathologica Communications·Niklas von SpreckelsenChristian Mawrin
Sep 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ana HipólitoJacinta Serpa
Apr 7, 2020·Scientific Reports·Nishtha PandeyP K Vinod
Nov 12, 2020·Cancer Communications·Zhenye TangJinfang Zhang
Dec 4, 2020·Redox Biology·Anna-Theresa MellisGuenter Schwarz
Nov 2, 2019·Molecular Metabolism·Peter KreuzalerMariia Yuneva
Dec 17, 2020·International Journal of Molecular Sciences·Antonio BouthelierJulián Aragonés
Apr 4, 2021·Journal of Clinical Medicine·Hiroko KatoKenji Izumi
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mei HanTao Su
Nov 28, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Gabriela L OliveiraPaulo J Oliveira
Apr 18, 2021·Oncogene·Joseph Eniafe, Shuai Jiang
Jul 6, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Mohammad MalekanFateme Sheida
May 18, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Antonio Bouthelier, Julián Aragonés

❮ Previous
Next ❯