10779/crick.12620531.v1 Olatz Arrizabalaga Olatz Arrizabalaga Leire Moreno-Cugnon Leire Moreno-Cugnon Jaione Auzmendi-Iriarte Jaione Auzmendi-Iriarte Paula Aldaz Paula Aldaz Inmaculada Ibañez de Cáceres Inmaculada Ibañez de Cáceres Laura Garros-Regulez Laura Garros-Regulez Veronica Moncho-Amor Veronica Moncho-Amor Sergio Torres-Bayona Sergio Torres-Bayona Olga Pernía Olga Pernía Laura Pintado-Berninches Laura Pintado-Berninches Patricia Carrasco-Ramirez Patricia Carrasco-Ramirez María Cortes-Sempere María Cortes-Sempere Rocío Rosas Rocío Rosas Pilar Sanchez-Gomez Pilar Sanchez-Gomez Irune Ruiz Irune Ruiz Helena Caren Helena Caren Steven Pollard Steven Pollard Idoia Garcia Idoia Garcia Angel-Ayuso Sacido Angel-Ayuso Sacido Robin Lovell-Badge Robin Lovell-Badge Cristobal Belda-Iniesta Cristobal Belda-Iniesta Nicolas Sampron Nicolas Sampron Rosario Perona Rosario Perona Ander Matheu Ander Matheu High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response The Francis Crick Institute 2020 Lovell-Badge FC001107 0601 Biochemistry and Cell Biology 0604 Genetics 1112 Oncology and Carcinogenesis 2020-07-15 10:57:05 Journal contribution https://crick.figshare.com/articles/journal_contribution/High_expression_of_MKP1_DUSP1_counteracts_glioma_stem_cell_activity_and_mediates_HDAC_inhibitor_response/12620531 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.