title: 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.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiorelli
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kupp
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Szeto
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Costanza
authors.initials: C
authors.lastname: Lo Cascio
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Maire
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Alberta
authors.affiliation: Division of Neuropathology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Eschbacher
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Institute, Phoenix, AZ 85004, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Sanai
authors.affiliation: Division of Neurobiology, Barrow Brain Tumor Research Center, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: shwetal.mehta@dignityhealth.org.
authors.forename: Shwetal
authors.initials: S
authors.lastname: Mehta
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D000076104:Oligodendrocyte Transcription Factor 2 / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: D018960:Hyaluronan Receptors; C405708:OLIG2 protein, human; D000076104:Oligodendrocyte Transcription Factor 2; D016212:Transforming Growth Factor beta; D000071799:Zinc Finger E-box-Binding Homeobox 1