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 aspart...

Descripción completa

Detalles Bibliográficos
Autores: Meléndez-Rodríguez, Florinda, Urrutia, Andrés A., Lorendeau, Doriane, Rinaldi, Gianmarco, Roche, Olga, Böğürcü-Seidel, Nuray, Ortega-Muelas, Marta, Mesa-Ciller, Claudia, Turiel, Guillermo, Bouthelier, Antonio, Hernansanz-Agustín, Pablo, Elorza, Ainara, Escasany, Elia, Yang Li, Qilong Oscar, Torres-Capelli, Mar, Tello, Daniel, Fuertes, Esther, Fraga, Enrique, Martínez-Ruiz, Antonio, Pérez, Belén, Giménez-Bachs, José M., Salinas-Sánchez, Antonio S., Acker, Till, Sánchez-Prieto, Ricardo, Fendt, Sarah-Maria, De Bock, Katrien, Aragonés, Julián
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/188787
Acceso en línea:http://hdl.handle.net/10261/188787
Access Level:acceso abierto
Palabra clave:HIF1α
Glutamine
Aspartate biosynthesis
GOT1
GOT2
Cancer
Proliferation
Oxygen
Renal cell carcinoma
Descripción
Sumario: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.

Similares en LA Referencia