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  • EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance.

EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance.

Nature communications (2016-07-30)
C Depner, H Zum Buttel, N Böğürcü, A M Cuesta, M R Aburto, S Seidel, F Finkelmeier, F Foss, J Hofmann, K Kaulich, S Barbus, M Segarra, G Reifenberger, B K Garvalov, T Acker, A Acker-Palmer
ABSTRACT

Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-SV40 T Antigen (Ab-2) Mouse mAb (PAb416), liquid, clone PAb416, Calbiochem®
Sigma-Aldrich
Anti-Nuclei Antibody, clone 3E1.3, clone 3E1.3, Chemicon®, from mouse
Sigma-Aldrich
Anti-ZEB2 antibody produced in rabbit, affinity isolated antibody