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

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 essentia...

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Published in:	Cell reports (Cambridge) 2016-07, Vol.16 (4), p.950-966
Main Authors:	Singh, Shiv K., Fiorelli, Roberto, Kupp, Robert, Rajan, Sindhu, Szeto, Emily, Lo Cascio, Costanza, Maire, Cecile L., Sun, Yu, Alberta, John A., Eschbacher, Jennifer M., Ligon, Keith L., Berens, Michael E., Sanai, Nader, Mehta, Shwetal
Format:	Article
Language:	eng
Subjects:	Animals Cell Line, Tumor Cell Proliferation - genetics Glioblastoma - genetics Glioblastoma - pathology Humans Hyaluronan Receptors - genetics Mice Mice, Nude Neoplasm Invasiveness - genetics Neoplasm Invasiveness - 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
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Summary:	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 OLIG2S10, 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. [Display omitted] •Glioma cells expressing unphosphorylated OLIG2 are highly invasive•Unphosphorylated OLIG2 upregulates the TGF-β2 pathway and activates invasion genes•Inhibition of the TGF-β pathway blocks OLIG2-mediated invasion•Phospho-OLIG2 suppresses TGF-β2-mediated invasion Singh et al. show that the phosphorylation status of a CNS-specific transcription factor, OLIG2, dictates the switch from the proliferative to invasive phenotype in glioblastoma. Unphosphorylated OLIG2 induces invasion through upregulation of the TGF-β2 pathway. The authors provide a putative mechanism through which OLIG2 regulates both proliferation and invasion in GBM cells.
ISSN:	2211-1247 2211-1247