期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 126, 期 5, 页码 1745-1758出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78815
关键词
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资金
- NIH [R01 DK 079962, R01 CA 168393, P01 CA163227, P50 CA090381, K99 CA166507]
- Department of Defense Prostate Cancer Research Program [W81XWH-12-1-0158, W81XWH-15-1-0151]
- Prostate Cancer Foundation
- Koch Institute for Integrative Cancer Research at MIT
- Dana-Farber/Harvard Cancer Center
- American Association of Cancer Research [14-40-38-MA]
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 beta-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/beta-catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy.
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