Arrizabalaga, OlatzMoreno-Cugnon, LeireAuzmendi-Iriarte, JaioneAldaz, PaulaIbanez de Caceres, InmaculadaGarros-Regulez, LauraMoncho-Amor, VeronicaTorres-Bayona, SergioPernía, OlgaPintado-Berninches, LauraCarrasco-Ramirez, PatriciaCortes-Sempere, MaríaRosas, RocíoSánchez-Gómez, PilarRuiz, IruneCaren, HelenaPollard, StevenGarcia, IdoiaSacido, Angel-AyusoLovell-Badge, RobinBelda-Iniesta, CristobalSampron, NicolasPerona, RosarioMatheu, Ander2019-07-122019-07-122017Oncogenesis. 2017 Dec 14;6(12):4012157-9024http://hdl.handle.net/20.500.12105/7896The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti-tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma.engVoRhttp://creativecommons.org/licenses/by/4.0/Atribución 4.0 Internacional2928479861240110.1038/s41389-017-0003-9Oncogenesisopen access