(GBM) is the most common primary tumor of the central nervous system. Despite continuing efforts to improve treatment over the last two decades and advances in microsurgery, radio- and chemotherapy, median survival of patients remained limited at ~14 months after diagnosis 
. GBM is a highly aggressive tumor characterized by rapid growth and extensive infiltration of adjacent brain areas. Overall, GBM results in more years of life lost than any other cancer type, cancer-related death is the case in nearly all patients 
Notch receptors are evolutionary conserved transmembrane receptors which convey extracellular signals across the cell membrane and trigger signal cascades regulating gene expression. Notch activation has been implicated as a positive determinant of cancer formation in T cell acute lymphoblastic leukemia (T-ALL), primary melanomas, breast cancer and gliomas 
. Furthermore, Notch signaling was shown to control proliferation and apoptosis in gliomas 
, to promote glioma cell migration and invasion 
and to promote radio resistance in glioma stem-like cells 
. Blocking Notch signaling enhanced standard chemo-therapy 
and depleted the glioma initiating cell pool 
. Notch ligands provided by endothelial cells induce the self-renewal of cancer stem-like cells in glioblastoma 
. Previous studies have also shown that loss of Notch2 positively predicts patient survival in subgroups of high grade glial brain tumors 
. An additional mechanism by which Notch mediates tumor aggressiveness is by the induction of Tenascin-C – an extracellular glycoprotein which correlates with malignancy in glioblastoma and other cancers 
– by the Notch canonical co-activator RBPJκ 
. The role of canonical Notch signaling in cancer development, progression and metastasis is intensively studied and evidence is pointing to an oncogenic role of Notch in glioblastoma. However, the role of the non-canonical signaling pathway via Deltex in these mechanisms is still ill defined.
Deltex is a Notch interacting protein which contains a basic region at the N-terminus where it binds to the ankyrin repeats of the intracellular domain of Notch. Deltex has been proposed to regulate Notch activity by antagonizing the interaction between Notch and Suppressor of Hairless 
. In mammalian cells, DTX1
has been shown to be a transcriptional target of Notch itself suggesting a positive feedback loop between Notch and DTX1. However, Deltex protein family members contain a RING finger domain at their C-terminus with E3 ubiquitin ligase activity. Deltex has been shown to be part of a three protein complex (containing Notch, Deltex and non-visual β-arrestin) mediating the degradation of the intracellular Notch receptor through a ubiquitination-dependent pathway. Loss-of-function mutations provided in vivo
evidence for the functional relation of Deltex, Notch and non-visual β-arrestin in Drosophila wing development 
. Together, Deltex appears to act as a signal repressor or as a mediator of negative feedback for Notch signaling in mammals.
Deltex also exerts its function on Notch independent targets. DTX1 has been shown to exert E3 ubiquitin ligase activity on other protein substrates, such as the mitogen-activated protein kinase signaling component MAP kinase kinase kinase 1 (MEKK1). Targeted MEKK1 degradation by Deltex suppresses the activation of T-cells 
. In mice, three new ligands to the Notch receptor family have been identified which signal specifically through the DTX1 pathway 
independently of RBPJκ and MAML1 and one of these ligands (DNER) has been implicated in non-canonical regulation of glioma inducing cells 
. However, the genes involved in this pathway remain ill-defined 
. In summary, Deltex constitutes a distinct, cell context-dependent Notch signaling pathway.
Regarding the cellular origin of gliomagenesis, several findings suggest progenitor or adult stem cells as possible founder cells of intracranial neoplasms 
. Most interestingly, Deltex has been shown to block the transcription factor MASH1 in neural progenitor cells by binding to p300 and thereby blocking differentiation of these cells. This differentiation block was shown to be independent of canonical Notch signaling via RBPJκ 
. Furthermore, a Deltex mediated block of neural differentiation has been shown in microchaetae sensory precursors in Drosophila indicating a conserved role for Deltex as a regulator of differentiation in neuroglial tissues 
In this study we provide evidence that DTX1 has an oncogenic role in high grade glioma cell lines. We provide molecular insight in how a modulation of DTX1 levels changes the signaling networks in cancer cells and relate these findings to changes in the proliferative, migratory and clonogenic potential. We identify a set of genes specifically controlled by this non-canonical Notch signaling pathway and its impact on tumor phenotype and aggressiveness. Finally, low DTX1 expression levels correlate with longer survival in GBM and breast cancer patients.