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. Kim & 2 others Ralf Kittler, Robert M. Bachoo

Research output: Contribution to journalArticle

24 Citations (Scopus)

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

Fingerprint

Receptor Protein-Tyrosine Kinases
Glioblastoma
Oncogenes
Glioma
Networks (circuits)
Tumors
Transcription Factors
Plicamycin
Genetic Suppression
Gene Regulatory Networks
Oligodendroglia
Astrocytes
Zinc
Neoplasms
Down-Regulation
Genes
Cell Proliferation
Mutation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Singh, D. K., Kollipara, R. K., Vemireddy, V., Yang, X. L., Sun, Y., Regmi, N., ... 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

Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma. / Singh, Dinesh K.; Kollipara, Rahul K.; Vemireddy, Vamsidara; Yang, Xiao Li; Sun, Yuxiao; Regmi, Nanda; Klingler, Stefan; Hatanpaa, Kimmo J.; Raisanen, Jack; Cho, Steve K.; Sirasanagandla, Shyam; Nannepaga, Suraj; Piccirillo, Sara; Mashimo, Tomoyuki; Wang, Shan; Humphries, Caroline G.; Mickey, Bruce; Maher, Elizabeth A.; Zheng, Hongwu; Kim, Ryung S.; Kittler, Ralf; Bachoo, Robert M.

In: Cell Reports, Vol. 18, No. 4, 24.01.2017, p. 961-976.

Research output: Contribution to journalArticle

Singh, DK, Kollipara, RK, Vemireddy, V, Yang, XL, Sun, Y, Regmi, N, Klingler, S, Hatanpaa, KJ, Raisanen, J, Cho, SK, Sirasanagandla, S, Nannepaga, S, Piccirillo, S, Mashimo, T, Wang, S, Humphries, CG, Mickey, B, Maher, EA, Zheng, H, Kim, RS, Kittler, R & Bachoo, RM 2017, 'Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma', Cell Reports, vol. 18, no. 4, pp. 961-976. https://doi.org/10.1016/j.celrep.2016.12.064
Singh DK, Kollipara RK, Vemireddy V, Yang XL, Sun Y, Regmi N et al. Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma. Cell Reports. 2017 Jan 24;18(4):961-976. https://doi.org/10.1016/j.celrep.2016.12.064
Singh, Dinesh K. ; Kollipara, Rahul K. ; Vemireddy, Vamsidara ; Yang, Xiao Li ; Sun, Yuxiao ; Regmi, Nanda ; Klingler, Stefan ; Hatanpaa, Kimmo J. ; Raisanen, Jack ; Cho, Steve K. ; Sirasanagandla, Shyam ; Nannepaga, Suraj ; Piccirillo, Sara ; Mashimo, Tomoyuki ; Wang, Shan ; Humphries, Caroline G. ; Mickey, Bruce ; Maher, Elizabeth A. ; Zheng, Hongwu ; Kim, Ryung S. ; Kittler, Ralf ; Bachoo, Robert M. / Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma. In: Cell Reports. 2017 ; Vol. 18, No. 4. pp. 961-976.
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