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

Research output: Contribution to journalArticle

  • 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
  • Idoia Garcia
  • Angel-Ayuso Sacido
  • Robin Lovell-Badge
  • Cristobal Belda-Iniesta
  • Nicolas Sampron
  • Rosario Perona
  • Ander Matheu

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Original languageEnglish
Pages (from-to)401
Issue number12
Early online date14 Dec 2017
Publication statusE-pub ahead of print - 14 Dec 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.

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  • Journal Article

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