@article{2fc51423561846ab8e8101370fc76906,
title = "Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma",
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.",
keywords = "astrocyte, brain, cancer, glioblastoma, oncogene, stem cells, targeted therapy, transcription factor",
author = "Singh, {Dinesh K.} and Kollipara, {Rahul K.} and Vamsidara Vemireddy and Yang, {Xiao Li} and Yuxiao Sun and Nanda Regmi and Stefan Klingler and Hatanpaa, {Kimmo J.} and Jack Raisanen and Cho, {Steve K.} and Shyam Sirasanagandla and Suraj Nannepaga and Sara Piccirillo and Tomoyuki Mashimo and Shan Wang and Humphries, {Caroline G.} and Bruce Mickey and Maher, {Elizabeth A.} and Hongwu Zheng and Kim, {Ryung S.} and Ralf Kittler and Bachoo, {Robert M.}",
note = "Funding Information: We thank the McDermott Next-Generation Sequencing Core for performing ChIP-seq and the Texas Advanced Computing Center for providing computing resources. We are also grateful to Drs. John Albert and Charles Stiles (Dana-Farber Cancer Institute) for the Olig2 shRNA plasmid and to AROG Pharmaceuticals for providing crenolanib. This study was supported by National Institutes of Health (NIH) grant R01NS065195 (R.M.B.), Simmons Cancer Center NIH support grant 5P30CA142543 (R.M.B.), Cancer Prevention and Research Institute of Texas (CPRIT) award R1002 (R.K.), and philanthropic funds from the Annette Strauss Center for Neuro-Oncology, William Conley and Family Fund, Miller Family Fund in Neuro-oncology, and the Beth Kahn Wings and Roots Foundation, all at the University of Texas Southwestern Medical Center (R.M.B.). R.K. is a CPRIT Scholar in Cancer Research and a John L. Roach Scholar in Biomedical Research. Publisher Copyright: {\textcopyright} 2017 The Authors",
year = "2017",
month = jan,
day = "24",
doi = "10.1016/j.celrep.2016.12.064",
language = "English (US)",
volume = "18",
pages = "961--976",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}
