Title | Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Singh DK, Kollipara RK, Vemireddy V, Yang X-L, 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 |
Journal | Cell Rep |
Volume | 18 |
Issue | 4 |
Pagination | 961-976 |
Date Published | 2017 01 24 |
ISSN | 2211-1247 |
Keywords | Animals, Astrocytes, Brain, Brain Neoplasms, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Down-Regulation, ErbB Receptors, Gefitinib, Glioblastoma, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Grading, Oligodendrocyte Transcription Factor 2, Plasmids, Plicamycin, Quinazolines, Receptor, Platelet-Derived Growth Factor alpha, RNA Interference, SOXB1 Transcription Factors, Zinc Finger E-box-Binding Homeobox 1 |
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. |
DOI | 10.1016/j.celrep.2016.12.064 |
Alternate Journal | Cell Rep |
PubMed ID | 28122245 |
PubMed Central ID | PMC5321610 |
Grant List | P30 CA045508 / CA / NCI NIH HHS / United States P30 CA142543 / CA / NCI NIH HHS / United States R01 NS065195 / NS / NINDS NIH HHS / United States |
Related Faculty:
Hongwu Zheng, Ph.D.