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      β-Catenin: oncogenic role and therapeutic target in cervical cancer

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          Abstract

          Cervical cancer is a common and fatal malignancy of the female reproductive system. Human papillomavirus (HPV) is the primary causal agent for cervical cancer, but HPV infection alone is insufficient to cause the disease. Actually, most HPV infections are sub-clinical and cleared spontaneously by the host immune system; very few persist and eventually develop into cervical cancer. Therefore, other host or environmental alterations could also contribute to the malignant phenotype. One of the candidate co-factors is the β-catenin protein, a pivotal component of the Wnt/β-catenin signaling pathway. β-Catenin mainly implicates two major cellular activities: cell–cell adhesion and signal transduction. Recent studies have indicated that an imbalance in the structural and signaling properties of β-catenin leads to various cancers, such as cervical cancer. In this review, we will systematically summarize the role of β-catenin in cervical cancer and provide new insights into therapeutic strategies.

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          Most cited references88

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          Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

          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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            Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors.

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              Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity.

              Increased transcriptional activity of beta-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation is poorly understood. We have demonstrated that AKT, which is activated downstream from epidermal growth factor receptor signaling, phosphorylates beta-catenin at Ser552 in vitro and in vivo. AKT-mediated phosphorylation of beta-catenin causes its disassociation from cell-cell contacts and accumulation in both the cytosol and the nucleus and enhances its interaction with 14-3-3zeta via a binding motif containing Ser552. Phosphorylation of beta-catenin by AKT increases its transcriptional activity and promotes tumor cell invasion, indicating that AKT-dependent regulation of beta-catenin plays a critical role in tumor invasion and development.
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                Author and article information

                Contributors
                wangmin0000@csu.edu.cn
                Journal
                Biol Res
                Biol. Res
                Biological Research
                BioMed Central (London )
                0716-9760
                0717-6287
                5 August 2020
                5 August 2020
                2020
                : 53
                : 33
                Affiliations
                GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Laboratory Medicine, The Second Xiangya Hospital, , Central South University, ; Changsha, 410011 Hunan China
                Author information
                http://orcid.org/0000-0002-3420-4031
                Article
                301
                10.1186/s40659-020-00301-7
                7405349
                32758292
                f3518aed-b61d-422f-aff6-0db242956a8d
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 28 April 2020
                : 28 July 2020
                Funding
                Funded by: the Natural Science Foundation of Hunan Province
                Award ID: No.2019JJ40426
                Award ID: No.2019JJ40418
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                β-catenin,cervical cancer,cell–cell adhesion,wnt signaling pathway

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