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- Title
High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response.
- Authors
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; Ruiz, Irune; Caren, Helena; Pollard, Steven; Garcia, Idoia; Sacido, Angel-Ayuso; Lovell-Badge, Robin
- Abstract
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.
- Publication
Oncogenesis, 2017, Vol 6, Issue 12, p1
- ISSN
2157-9024
- Publication type
Article
- DOI
10.1038/s41389-017-0003-9