Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

Singh, D. K., Kollipara, R. K., Vemireddy, V., Yang, X. L., Sun, Y., Regmi, N., Klingler, S., Hatanpaa, K. J., Raisanen, J., Cho, S. K., Sirasanagandla, S., Nannepaga, S., Piccirillo, S., Mashimo, T., Wang, S., Humphries, C. G., Mickey, B., Maher, E. A., Zheng, H., Kim, R. S., Kittler, R., Bachoo, R. M. (January 2017) Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma. Cell Rep, 18 (4). pp. 961-976. ISSN 2211-1247 (Electronic)

URL: https://www.ncbi.nlm.nih.gov/pubmed/28122245
DOI: 10.1016/j.celrep.2016.12.064

Abstract

Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1), which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

Item Type: Paper
Uncontrolled Keywords: astrocyte brain cancer glioblastoma oncogene stem cells targeted therapy transcription factor
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > astrocytes
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > astrocytes
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > astrocytes

diseases & disorders > cancer > cancer types > glioblastoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL labs > Zheng lab
Depositing User: Matt Covey
Date: 24 January 2017
Date Deposited: 10 Jan 2018 17:05
Last Modified: 10 Jan 2018 17:05
PMCID: PMC5321610
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35803

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