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Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 44, p. 22189-22195Article in journal (Refereed) Published
Abstract [en]

The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple Wnt ligands, including WNT7B, which increases TCF/LEF-dependent transcription without activating Wnt coreceptor LRP6 or beta-catenin. Proximity ligation and functional complementation assays identified several transcription regulators, including YY1, JUN, and DDX5, as cofactors required for FOXB2-dependent pathway activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 controls Wnt signaling and neuroendocrine differentiation of prostate cancer cell lines. Our results suggest that FOXB2 is a tissue-specific Wnt activator that promotes the malignant transformation of prostate cancer.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2019. Vol. 116, no 44, p. 22189-22195
Keywords [en]
FOXB2; Wnt signaling; forkhead; prostate cancer
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-162065DOI: 10.1073/pnas.1906484116ISI: 000493720200039PubMedID: 31611391OAI: oai:DiVA.org:liu-162065DiVA, id: diva2:1371350
Note

Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation

Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2019-11-19

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