List of communications


ZBTB18 Methylation Promotes Mesenchymal Transformation in Glioblastoma

Vita Fedele, Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany; Fangping Dai, Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany; Anie Priscilla Masilaman, Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany; Eva Bug, Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany; Leonardo Platania, Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany ,Hyunsoo Kim, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; Sven Nelander, Department of Immunology, Genetics and Pathology and Science for Life Laboratories, University of Uppsala, Uppsala, 75105, Sweden; Astrid Weyerbrock, Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany; Markus Bredel, Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35249, USA; Maria Stella Carro, 1Department of Neurosurgery, Neurocenter, and Comprehensive Cancer Center, University of Freiburg, Freiburg, D-79106, Germany


Over the past decade, glioblastoma subclasses with distinct differentiation characteristics and associated clinical outcome were identified. The mesenchymal subtype is characterized by a comparatively poor prognosis and inherent resistance to radiotherapy. ZBTB18 is a transcription factor that belongs to the Broad complex, Tramtrack, Bric à brac [BTB] or poxvirus and zing finger [POZ]-zinc finger (BTB/POZ-ZF) protein family and plays a crucial role in brain development and neuronal differentiation. Consistent with our previous study, which provided preliminary evidence of a role for ZBTB18 in a network of mesenchymal transformation in glioblastoma, our new data have discovered epigenetic silencing, that is promoter methylation, as a mechanism to downregulate ZBTB18 in this tumors. ZBTB18 promoter analysis by pyrosequencing identified a region which is specifically methylated in the mesenchymal subgroup and negatively correlated with ZBTB18 expression. Overexpression studies followed by gene set enrichment analysis (GSEA), using primary-glioblastoma derived cells showed an enrichment of the mesenchymal and proliferative gene signature previously described by Phillips and colleagues. Consistent with this, re-expression of ZBTB18 reduces cell proliferation, invasion and impairs tumor-forming ability. Overall, our results support a tumor suppressor role of ZBTB18 in the brain and identify promoter hypermethylation as a mechanism to silence ZBTB18 in the mesenchymal subtype of glioblastoma, which provides a new mechanistic opportunity to specifically target this tumor subclass.

Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., Miller, C. R., Ding, L., Golub, T., Mesirov, J. P., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98-110.

Phillips, H. S., Kharbanda, S., Chen, R., Forrest, W. F., Soriano, R. H., Wu, T. D., Misra, A., Nigro, J. M., Colman, H., Soroceanu, L., et al. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157-173.

Carro, M. S., Lim, W. K., Alvarez, M. J., Bollo, R. J., Zhao, X., Snyder, E. Y., Sulman, E. P., Anne, S. L., Doetsch, F., Colman, H., et al. (2010). The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318-325.

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