β-Catenin-Gli1 interaction regulates proliferation and tumor growth in medulloblastoma

Molecular Cancer

Short Communication

Rune Toftgård¹  Fabian T Schneider²  Karl H Plate³  Jenny Zinke³  Sonja Thom³  Stefan Liebner³  Nicole Ziegler³  Patrick N Harter⁴ 

[1] Center for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden;Center for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden;Current address: Department of Neuropathology, Institute of Pathology and Pathological Anatomy, Technical University Munich, Trogerstrasse 18, 81675, Munich, Germany;Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany;Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Frankfurt, Medical School, Heinrich-Hoffmann-Straße 7, 60528, Frankfurt, Germany;German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany;

关键词: β-catenin;    Gli1;    Interaction;    Medulloblastoma;    Senescence;    p21;    LiCl;    GSK-3β;   

DOI  :  10.1186/s12943-015-0294-4

 received in 2014-07-24, accepted in 2015-01-12,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe 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.FindingsHere 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.ConclusionWe 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.

【 授权许可】

Unknown   
© Zinke et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.