2024-03-28T23:30:30Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1887872022-08-17T07:28:45Zcom_10261_22com_10261_1com_10261_79col_10261_275col_10261_332
HIF1α suppresses tumor cell proliferation through inhibition of aspartate biosynthesis
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
Agencia Estatal de Investigación (España)
Ministerio de Economía y Competitividad (España)
Comunidad de Madrid
Fundació La Marató de TV3
European Commission
Research Foundation - Flanders
Universidad de Castilla La Mancha
Ministerio de Educación y Ciencia (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Fundación Leticia Castillejo
HIF1α
Glutamine
Aspartate biosynthesis
GOT1
GOT2
Cancer
Proliferation
Oxygen
Renal cell carcinoma
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.
This work was supported by grants from Ministerio de Economia 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 Economia 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).
Peer reviewed
2019-08-22T06:39:36Z
2019-08-22T06:39:36Z
2019
artículo
http://purl.org/coar/resource_type/c_6501
Cell Reports 26(9): 2257-2265.e4
http://hdl.handle.net/10261/188787
10.1016/j.celrep.2019.01.106
2211-1247
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003130
http://dx.doi.org/10.13039/100012818
http://dx.doi.org/10.13039/100008666
http://dx.doi.org/10.13039/501100007480
http://dx.doi.org/10.13039/501100011033
30811976
en
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
SAF2017-90794-REDT/AEI/10.13039/501100011033
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76815-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-90794-REDT
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-64215-R
Publisher's version
https://doi.org/10.1016/j.celrep.2019.01.106
Sí
open
Elsevier