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

Journal article
Authors O. Arrizabalaga
L. Moreno-Cugnon
J. Auzmendi-Iriarte
P. Aldaz
II de Caceres,
L. Garros-Regulez
V. Moncho-Amor
S. Torres-Bayona
O. Pernia
L. Pintado-Berninches
P. Carrasco-Ramirez
M. Cortes-Sempere
R. Rosas
P. Sanchez-Gomez
I. Ruiz
Helena Carén
S. Pollard
I. Garcia
A. A. Sacido
R. Lovell-Badge
C. Belda-Iniesta
N. Sampron
R. Perona
A. Matheu
Published in Oncogenesis
Volume 6
ISSN 2157-9024
Publication year 2017
Published at Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Pathology
Language en
Links dx.doi.org/10.1038/s41389-017-0003-...
Keywords protein-kinase phosphatase-1, tumor-initiating cells, human, breast-cancer, n-terminal kinase, p38 mapk, temozolomide resistance, human glioblastoma, pivotal role, lung-cancer, activation, Oncology
Subject categories Cancer and Oncology

Abstract

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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