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Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression
Bing Song, … , Ximing Yang, Jindan Yu
Bing Song, … , Ximing Yang, Jindan Yu
Published December 4, 2018
Citation Information: J Clin Invest. 2019;129(2):569-582. https://doi.org/10.1172/JCI122367.
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Research Article Genetics Oncology

Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression

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Abstract

Prostate cancer (PC) progressed to castration resistance (CRPC) is a fatal disease. CRPC tumors develop resistance to new-generation antiandrogen enzalutamide through lineage plasticity, characterized by epithelial-mesenchymal transition (EMT) and a basal-like phenotype. FOXA1 is a transcription factor essential for epithelial lineage differentiation. Here, we demonstrate that FOXA1 loss leads to remarkable upregulation of transforming growth factor beta 3 (TGFB3), which encodes a ligand of the TGF-β pathway. Mechanistically, this is due to genomic occupancy of FOXA1 on an upstream enhancer of the TGFB3 gene to directly inhibit its transcription. Functionally, FOXA1 downregulation induces TGF-β signaling, EMT, and cell motility, which is effectively blocked by the TGF-β receptor I inhibitor galunisertib (LY2157299). Tissue microarray analysis confirmed reduced levels of FOXA1 protein and a concordant increase in TGF-β signaling, indicated by SMAD2 phosphorylation, in CRPC as compared with primary tumors. Importantly, combinatorial LY2157299 treatment sensitized PC cells to enzalutamide, leading to synergistic effects in inhibiting cell invasion in vitro and xenograft CRPC tumor growth and metastasis in vivo. Therefore, our study establishes FOXA1 as an important regulator of lineage plasticity mediated in part by TGF-β signaling, and supports a novel therapeutic strategy to control lineage switching and potentially extend clinical response to antiandrogen therapies.

Authors

Bing Song, Su-Hong Park, Jonathan C. Zhao, Ka-wing Fong, Shangze Li, Yongik Lee, Yeqing A. Yang, Subhasree Sridhar, Xiaodong Lu, Sarki A. Abdulkadir, Robert L. Vessella, Colm Morrissey, Timothy M. Kuzel, William Catalona, Ximing Yang, Jindan Yu

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Figure 7

Enzalutamide and LY2157299 drug combination blocks xenograft prostate tumor growth and metastasis.

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Enzalutamide and LY2157299 drug combination blocks xenograft prostate tu...
(A) Castrated mice bearing VCaP xenografts received vehicle, Enz (oral, 10 mg/kg) alone or in combination with LY2157299 (oral, 75 mg/kg) 5 days per week for 33 days. Mean tumor volume ± SEM is shown. Significance was calculated using ANOVA, P < 0.05. (B) At the endpoint, mice were euthanized and femurs (bone marrow) were dissected. Genomic DNA were isolated and analyzed for metastasized cells by measuring human Alu sequence (by Alu-qPCR). (C and D) Immunohistochemistry was performed in tumor sections isolated from xenograft mice with the indicated antibodies and H&E staining. Representative images are shown. Scale bars: 50 μm.
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