Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

Dinesh K. Singh, Rahul K. Kollipara, Vamsidara Vemireddy, Xiao Li Yang, Yuxiao Sun, Nanda Regmi, Stefan Klingler, Kimmo J. Hatanpaa, Jack Raisanen, Steve K. Cho, Shyam Sirasanagandla, Suraj Nannepaga, Sara Piccirillo, Tomoyuki Mashimo, Shan Wang, Caroline G. Humphries, Bruce Mickey, Elizabeth A. Maher, Hongwu Zheng, Ryung S. KimRalf Kittler, Robert M. Bachoo

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)961-976
Number of pages16
JournalCell Reports
Volume18
Issue number4
DOIs
StatePublished - Jan 24 2017

Keywords

  • astrocyte
  • brain
  • cancer
  • glioblastoma
  • oncogene
  • stem cells
  • targeted therapy
  • transcription factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    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., ... Bachoo, R. M. (2017). Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma. Cell Reports, 18(4), 961-976. https://doi.org/10.1016/j.celrep.2016.12.064