Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7896
High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response
Arrizabalaga, Olatz | Moreno-Cugnon, Leire | Auzmendi-Iriarte, Jaione | Aldaz, Paula | Ibanez de Caceres, Inmaculada | Garros-Regulez, Laura | Moncho-Amor, Veronica | Torres-Bayona, Sergio | Pernía, Olga | Pintado-Berninches, Laura | Carrasco-Ramirez, Patricia | Cortes-Sempere, María | Rosas, Rocío | Sanchez-Gomez, Pilar ISCIII | Ruiz, Irune | Caren, Helena | Pollard, Steven | Garcia, Idoia | Sacido, Angel-Ayuso | Lovell-Badge, Robin | Belda-Iniesta, Cristobal ISCIII | Sampron, Nicolas | Perona, Rosario | Matheu, Ander
Oncogenesis. 2017 Dec 14;6(12):401
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.
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