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High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response

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posted on 15.07.2020 by Olatz Arrizabalaga, Leire Moreno-Cugnon, Jaione Auzmendi-Iriarte, Paula Aldaz, Inmaculada Ibañez de Cáceres, Laura Garros-Regulez, Veronica Moncho-Amor, Sergio Torres-Bayona, Olga Pernía, Laura Pintado-Berninches, Patricia Carrasco-Ramirez, María Cortes-Sempere, Rocío Rosas, Pilar Sanchez-Gomez, Irune Ruiz, Helena Caren, Steven Pollard, Idoia Garcia, Angel-Ayuso Sacido, Robin Lovell-Badge, Cristobal Belda-Iniesta, Nicolas Sampron, Rosario Perona, Ander Matheu
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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