FZD8, a target of p53, promotes bone metastasis in prostate cancer by activating canonical Wnt/β-catenin signaling

• Published in: Cancer letters Vol. 402; pp. 166 - 176
• Main Authors: Li, Qiji, Ye, Liping, Xin, Zhang, Wang, Min, Lin, Chuyong, Huang, Shuai, Guo, Wei, Lai, Yingrong, Du, Hong, Li, Jun, Song, Libing, Peng, Xinsheng
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.08.2017; Elsevier Limited
• Subjects: Aged; Animals; Binding Sites; Biotechnology; Bone cancer; Bone metastasis; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Canonical Wnt/β-catenin; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell migration; Cell Movement; Disease Progression; FZD8; Gene Expression Regulation, Neoplastic; Gene Silencing; Hematology, Oncology and Palliative Medicine; Humans; Incidence; Male; Men; Metastases; Metastasis; Mice, Inbred BALB C; Mice, Nude; Molecular modelling; Mortality; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; p53; p53 Protein; Patients; Phenotype; Promoter Regions, Genetic; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Binding; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Stem cells; Time Factors; Tissues; Transcription; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53 - metabolism; Wnt protein; Wnt Signaling Pathway; β-Catenin; FZD8; prostate cancer; bone metastasis; canonical Wnt/β-catenin; p53; Bone metastasis; Canonical Wnt/β-catenin; Prostate cancer
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.05.029

Abstract Prostate cancer (PCa) is the second most frequently diagnosed cancer among men and exhibits a high propensity to metastasize to bone. Currently, bone metastasis remains incurable, and therapies are limited. A better understanding of the molecular mechanisms involved in PCa bone metastasis is needed to develop more effective therapeutics for this disease. Herein, we reported that among the FZD family, FZD8 was robustly upregulated in bone-metastastic PCa cell lines and tissues. High levels of FZD8 expression were significantly positively associated with clinical tumor progression and bone metastasis. Furthermore, we found that overexpressing FZD8 promoted, whereas silencing FZD8 suppressed, PCa cell migration, invasion and stem cell-like phenotypes in vitro , through the activation of canonical Wnt/β-catenin signaling. Importantly, downregulation of FZD8 greatly suppressed the incidence of PCa bone metastasis in vivo . Moreover, wild-type p53 transcriptionally repressed FZD8 by directly interacting with the FZD8 promoter. Taken together, these findings uncover a novel mechanism for PCa bone metastasis, and indicate that FZD8 might represent a potential therapeutic target for PCa bone metastasis.