Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway.

Abstract

In glioblastoma, invasion and proliferation are presumed to be mutually exclusive events; however, the molecular mechanisms that mediate this switch at the cellular level remain elusive. Previously, we have shown that phospho-OLIG2, a central-nervous-system-specific transcription factor, is essential for tumor growth and proliferation. Here, we show that the modulation of OLIG2 phosphorylation can trigger a switch between proliferation and invasion. Glioma cells with unphosphorylated OLIG2(S10, S13, S14) are highly migratory and invasive, both in vitro and in vivo. Mechanistically, unphosphorylated OLIG2 induces TGF-β2 expression and promotes invasive mesenchymal properties in glioma cells. Inhibition of the TGF-β2 pathway blocks this OLIG2-dependent invasion. Furthermore, ectopic expression of phosphomimetic Olig2 is sufficient to block TGF-β2-mediated invasion and reduce expression of invasion genes (ZEB1 and CD44). Our results not only provide a mechanistic insight into how cells switch from proliferation to invasion but also offer therapeutic opportunities for inhibiting dissemination of gliomas.

• Authors: Shiv K Singh, Roberto Fiorelli, Robert Kupp, Sindhu Rajan, Emily Szeto, Costanza Lo Cascio, Cecile L Maire, Yu Sun, John A Alberta, Jennifer M Eschbacher, Keith L Ligon, Michael E Berens, Nader Sanai, Shwetal Mehta
• Journal: Cell reports (Cell Rep) Vol. 16 Issue 4 Pg. 950-966 (07 26 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27396340 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Hyaluronan Receptors
• OLIG2 protein, human
• Oligodendrocyte Transcription Factor 2
• Transforming Growth Factor beta
• Zinc Finger E-box-Binding Homeobox 1

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Glioblastoma (genetics, pathology)
• Humans
• Hyaluronan Receptors (genetics)
• Mice
• Mice, Nude
• Neoplasm Invasiveness (genetics, pathology)
• Oligodendrocyte Transcription Factor 2 (genetics)
• Phosphorylation (genetics)
• Protein Processing, Post-Translational (genetics)
• Signal Transduction (genetics)
• Transforming Growth Factor beta (genetics)
• Zinc Finger E-box-Binding Homeobox 1 (genetics)