title: SOX9 drives WNT pathway activation in prostate cancer.
abstract: 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.
authors.forename: Fen
authors.initials: F
authors.lastname: Ma
authors.forename: Huihui
authors.initials: H
authors.lastname: Ye
authors.forename: Housheng Hansen
authors.initials: HH
authors.lastname: He
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Gerrin
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Tanenbaum
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.forename: Adam G
authors.initials: AG
authors.lastname: Sowalsky
authors.forename: Lingfeng
authors.initials: L
authors.lastname: He
authors.forename: Hongyun
authors.initials: H
authors.lastname: Wang
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.forename: Xin
authors.initials: X
authors.lastname: Yuan
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D009363:Neoplasm Proteins; D011719:Pyrazines; D011725:Pyridines; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; C586458:LGK974