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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 6

Enzalutamide and LY2157299 drug combination synergistically inhibit prostate cancer cell invasion.

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Enzalutamide and LY2157299 drug combination synergistically inhibit pros...
(A) Western blot analysis of PSA and pSMAD2 in VCaP cells treated with 5 ng/ml TGF-β3, 10μM Enz, and/or 10 μM LY2157299 for 24 hours. (B) The relative PSA band intensity was quantified and normalized to GAPDH. (C and D) Matrigel assays of VCaP cells that were treated with vehicle control, 10 μM Enz, 10 μM LY2157299, or their combination in the absence (C) or presence of 5 ng/ml TGF-β3 ligand (D). (E) Matrigel assays of LNCaP-RII stable cells treated with vehicle control, 10 μM Enz, 10 μM LY2157299, or their combination. Original magnification, C–E: ×20.
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