SOX9 drives WNT pathway activation in prostate cancer
| Autor: | Sen Chen, Benjamin A. Tanenbaum, Xin Yuan, Adam G. Sowalsky, Steven P. Balk, Fen Ma, Lingfeng He, Hongyun Wang, Huihui Ye, Changmeng Cai, Sean J. Gerrin, Housheng Hansen He |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine endocrine system Frizzled Pyridines Mice Nude Mice SCID Biology Bioinformatics Mice 03 medical and health sciences Prostate cancer Transcription Factor 4 stomatognathic system Cell Line Tumor medicine Animals Humans Wnt Signaling Pathway Transcription factor Regulation of gene expression Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Wnt signaling pathway Prostatic Neoplasms LRP6 SOX9 Transcription Factor LRP5 General Medicine TCF4 medicine.disease Xenograft Model Antitumor Assays Neoplasm Proteins Gene Expression Regulation Neoplastic 030104 developmental biology Pyrazines embryonic structures Cancer research Transcription Factors Research Article |
| Zdroj: | Journal of Clinical Investigation. 126:1745-1758 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci78815 |
| Popis: | The transcription factor SOX9 is critical for prostate development, and dysregulation of SOX9 is implicated in prostate cancer (PCa). However, the SOX9-dependent genes and pathways involved in both normal and neoplastic prostate epithelium are largely unknown. Here, we performed SOX9 ChIP sequencing analysis and transcriptome profiling of PCa cells and determined that SOX9 positively regulates multiple WNT pathway genes, including those encoding WNT receptors (frizzled [FZD] and lipoprotein receptor-related protein [LRP] family members) and the downstream β-catenin effector TCF4. Analyses of PCa xenografts and clinical samples both revealed an association between the expression of SOX9 and WNT pathway components in PCa. Finally, treatment of SOX9-expressing PCa cells with a WNT synthesis inhibitor (LGK974) reduced WNT pathway signaling in vitro and tumor growth in murine xenograft models. Together, our data indicate that SOX9 expression drives PCa by reactivating the WNT/β−catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy. |
| Databáze: | OpenAIRE |
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