Suchergebnisse

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. ; O.A. (BFI_2011_195), L.G.-R. (PRE_2013_1_760), L.M.-C. (PRE_2014_1_92), and J.A.-I. (PRE_2016_1_0375) were each recipient of a predoctoral fellowship from the Department of Education, University and Research of the Basque Government, and P.A. from the Spanish Association Against Cancer (AECC Gipuzkoa). This work was supported by grants from the Instituto de Salud Carlos III and FEDER Funds (PI13/02277, PI14/01495, PI15/00186, CP16/00039, PI16/01580, DTS16/084), European Union (Marie Curie CIG 2012/712404, REFBIO13/BIOD/009, and 011), and AICR/WCR [13–1270]. ; Peer reviewed