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.