2024-03-28T18:58:50Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/78962023-10-06T14:37:21Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2109com_20.500.12105_2052col_20.500.12105_16974col_20.500.12105_16963col_20.500.12105_2110
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
2157-9024
http://hdl.handle.net/20.500.12105/7896
29284798
10.1038/s41389-017-0003-9
Oncogenesis
High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response