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TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 45, p. 192-207
Keywords [en]
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-161915DOI: 10.1016/j.ebiom.2019.06.046ISI: 000475860000026PubMedID: 31262711Scopus ID: 2-s2.0-85067957867OAI: oai:DiVA.org:umu-161915DiVA, id: diva2:1340885
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved

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Aripaka, KarthikGudey, Shyam KumarZang, GuangxiangSchmidt, AlexejÅhrling, Samaneh ShabaniÖsterman, LennartBergh, Andersvon Hofsten, JonasLandström, Maréne

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Aripaka, KarthikGudey, Shyam KumarZang, GuangxiangSchmidt, AlexejÅhrling, Samaneh ShabaniÖsterman, LennartBergh, Andersvon Hofsten, JonasLandström, Maréne
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Department of Medical BiosciencesPathologyMedical and Clinical GeneticsUmeå Centre for Molecular Medicine (UCMM)Department of Integrative Medical Biology (IMB)
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