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oai:repisalud.isciii.es:20.500.12105/78962025-06-13T08:13:35Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_16963col_20.500.12105_16974col_20.500.12105_19617

00925njm 22002777a 4500 dc Arrizabalaga, Olatz author Moreno-Cugnon, Leire author Auzmendi-Iriarte, Jaione author Aldaz, Paula author Ibanez de Caceres, Inmaculada author Garros-Regulez, Laura author Moncho-Amor, Veronica author Torres-Bayona, Sergio author Pernía, Olga author Pintado-Berninches, Laura author Carrasco-Ramirez, Patricia author Cortes-Sempere, María author Rosas, Rocío author Sánchez-Gómez, Pilar author Ruiz, Irune author Caren, Helena author Pollard, Steven author Garcia, Idoia author Sacido, Angel-Ayuso author Lovell-Badge, Robin author Belda-Iniesta, Cristobal author Sampron, Nicolas author Perona, Rosario author Matheu, Ander author 2017 The 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. Oncogenesis. 2017 Dec 14;6(12):401 10.1038/s41389-017-0003-9 2157-9024 Oncogenesis 29284798 http://hdl.handle.net/20.500.12105/7896 High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response