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Analysis of the transcriptional changes induced by DYRK1A inhibition in glioblastoma cells

Paloma Fernández-Martínez, Instituto de Medicina Molecular Aplicada (IMMA), Universidad CEU-San Pablo, Madrid, Spain;
Pilar Aguilera Sepúlveda, Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain
Pilar Sánchez-Gómez, Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain

Glioblastoma (GBM) is the most common malignant brain tumor and is characterized by intratumoral heterogeneity, invasive growth pattern and poor response to treatment. Microarray expression profiling has identified molecular subtypes as well as genes associated with GBM tumor grade and progression. One tumor class displaying neuronal lineage markers shows longer survival, while poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme.
Our group has recently determined that the growth and survival of EGFR-dependent GBMs is modulated by DYRK1A (Dual-specificity tyrosine(Y)-phosphorylation-Regulated Kinase 1A). Thus, we have demonstrated that genetic or pharmacological (in the presence of Harmine) inhibition of this kinase compromises the expansion of GBM cells, at least in part through the stimulation of EGFR degradation. Here we have performed a microarray analysis in order to elucidate the exact mechanism of DYRK1A function in GBM. IPA analysis revealed that cancer, respiratory disease, gene expression, molecular transport and cellular assembly and organization were ranked in the top of “Molecular and Cellular Functions” showing changes after DYRK1A downregulation (shRNA) or inhibition (Harmine). On the other hand, Axonal Guidance Signaling, Molecular Mechanisms of Cancer, Protein Kinase A Signaling, Colorectal Cancer Metastasis Signaling and Signaling by Rho Family GTPases, were among the top canonical pathways altered by DYRK1A blockade. Interestingly, the analysis also revealed the upregulation of mesenchymal markers (COL5A1, YKL-40, MMP9, CTGF) and the downregulation of proneural and proliferative markers (VCAN, CDKN1A, CCNE1, GLI3, TNFRSF21, TOP2A) after DYRK1A inhibition. We therefore decided to test DYRK1A expression in a panel of glioma biopsies. Accordingly, we have observed a high correlation between DYRK1A and proneural subtype markers and no correlation with some mesenchymal and proliferative markers. Our results suggest that DYRK1A could participate in GBM subclass determination and that therapeutic targeting of this kinase could have as a consequence the mesenchymalization of the tumor. Further analysis will help to determine the responsible mechanism for this transition as well as the consequences for potential DYRK1A targeting in GBMs.

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