title: β-Catenin-Gli1 interaction regulates proliferation and tumor growth in medulloblastoma.
abstract: BACKGROUND
  The Wnt/beta-catenin and the Hedgehog (Hh) pathway interact in various cell types while eliciting opposing or synergistic cellular effects. Both pathways are known as exclusive drivers of two distinct molecular subtypes of medulloblastoma (MB). In sonic hedgehog (Shh)-driven MB, activation of Wnt signaling has been shown to suppress tumor growth by either beta-catenin-dependent or -independent inhibition of Shh signaling. However, mechanistic insight in how beta-catenin inhibits the Hh pathway is not known.
  
  
  RESULTS
  Here we show that beta-catenin stabilization by the glycogen synthase kinase 3 inhibitor lithium chloride (LiCl) reduced growth of primary hedgehog-driven MB tumor spheres from patched heterozygous mice (Ptch(+/-)) in vitro. LiCl treatment of MB spheres down-regulated the Hh target Gli1, whereas the repressive Gli3 protein (Gli3R) was increased. Mechanistically, we show by co-immunoprecipitation and proximity ligation assay that stabilized beta-catenin physically interacts with Gli1, leading to Gli1 sequestration and inhibition of its transcriptional activity. Reduction of Hh signaling upon LiCl stimulation resulted in reduced proliferation, sphere self renewal, a G2/M arrest and induction of a senescent-like state, indicated by p21 upregulation and by increased staining of senescence-associated beta-galactosidase (SA-betaGal). Moreover, LiCl treatment of subcutaneously transplanted MB cells significantly reduced tumor initiation defined as "tumor take". Although tumor progression was similar, LiCl-treated tumors showed decreased mitotic figures and phospho-histone H3 staining.
  
  
  CONCLUSIONS
  We propose that beta-catenin stabilization increases its physical interaction with Gli1, leading to Gli1 degradation and inhibition of Hh signaling, thereby promoting tumor cell senescence and suppression of "tumor take" in mice.
authors: Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany. jenny.zinke@kgu.de.
authors: Jenny
authors: J
authors: Zinke
authors: Center for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden. fabian.t.schneider@tum.de.|Current address: Department of Neuropathology, Institute of Pathology and Pathological Anatomy, Technical University Munich, Trogerstrasse 18, 81675, Munich, Germany. fabian.t.schneider@tum.de.
authors: Fabian T
authors: FT
authors: Schneider
authors: Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany. patrick.harter@kgu.de.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. patrick.harter@kgu.de.
authors: Patrick N
authors: PN
authors: Harter
authors: Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany. sonja.thom@kgu.de.
authors: Sonja
authors: S
authors: Thom
authors: Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany. nicole.ziegler@kgu.de.
authors: Nicole
authors: N
authors: Ziegler
authors: Center for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden. rune.toftgard@ki.se.
authors: Rune
authors: R
authors: Toftgård
authors: Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany. plate@kgu.de.
authors: Karl H
authors: KH
authors: Plate
authors: Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany. stefan.liebner@kgu.de.
authors: Stefan
authors: S
authors: Liebner
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3
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