Frizzled-8 integrates Wnt-11 and transforming growth factor-β signaling in prostate cancer
File(s)s41467-018-04042-w.pdf (3.2 MB)
Published version
OA Location
Author(s)
Type
Journal Article
Abstract
Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-β/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-β-regulated complex with TGF-β receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-β signals in prostate cancer.
Date Issued
2018-05-01
Date Acceptance
2018-03-29
Citation
Nature Communications, 2018, 9
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
9
Copyright Statement
© The Author(s) 2018. This 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 license, and indicate if changes were made. The images or other third party
material in this article are included in the article
’
s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article
’
s Creative Commons license 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 license, visit
http://creativecommons.org/
licenses/by/4.0/
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 license, and indicate if changes were made. The images or other third party
material in this article are included in the article
’
s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article
’
s Creative Commons license 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 license, visit
http://creativecommons.org/
licenses/by/4.0/
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CONVERGENT EXTENSION MOVEMENTS
TGF-BETA
WNT/BETA-CATENIN
NONCANONICAL WNT
TRANSCRIPTIONAL ACTIVATION
MESENCHYMAL TRANSITION
XENOPUS-LAEVIS
MAJOR ROLE
CELLS
MECHANISMS
MD Multidisciplinary
Publication Status
Published
Article Number
1747