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      Wnt signaling in cancer

      review-article
      Author(s): 1 , 2 , 1 , 1 , 3 , *
      Publication date (Electronic):
      Journal: Oncogene
      Publisher: Nature Publishing Group

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          Abstract

          Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.

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          WNT signaling in bone homeostasis and disease: from human mutations to treatments.

          Roland Baron, Michaela Kneissel (2013)
          Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
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            Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

            Shih-Min A Huang, Yuji M. Mishina, Shanming Liu … (2009)
            The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
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              YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

              Luca Azzolin, Tito Panciera, Sandra Soligo … (2014)
              The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncogene
                Journal ID (iso-abbrev): Oncogene
                Title: Oncogene
                Publisher: Nature Publishing Group
                ISSN (Print): 0950-9232
                ISSN (Electronic): 1476-5594
                Publication date (Print): March 2017
                Publication date (Electronic): 12 September 2016
                Volume: 36
                Issue: 11
                Pages: 1461-1473
                Affiliations
                [1 ]German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics, Heidelberg University, Department Cell and Molecular Biology, Faculty of Medicine Mannheim , Heidelberg, Germany
                [2 ]Heidelberg University, Department of Internal Medicine II, Medical Faculty Mannheim , Mannheim, Germany
                [3 ]German Cancer Consortium (DKTK) , Heidelberg, Germany
                Author notes
                [* ]German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics , Im Neuenheimer Feld 580, Heidelberg, Germany. E-mail: m.boutros@ 123456dkfz.de
                [4]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-9458-817X
                Article
                Publisher Item ID: onc2016304
                DOI: 10.1038/onc.2016.304
                PMC ID: 5357762
                PubMed ID: 27617575
                SO-VID: 04c82855-8409-422a-bd0f-d0bdc254742c
                Copyright © Copyright © 2017 The Author(s)
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                Date received : 29 May 2016
                Date revision received : 07 July 2016
                Date accepted : 17 July 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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