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

Bing Song, Su Hong Park, Jonathan C. Zhao, Kawing W. 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*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)569-582
Number of pages14
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

LY-2157299
Castration
Androgen Antagonists
Prostatic Neoplasms
Epithelial-Mesenchymal Transition
Transforming Growth Factor beta
Tissue Array Analysis
Neoplasms
Heterografts
Cell Movement
Transcription Factors
Up-Regulation
Down-Regulation
Phosphorylation
Neoplasm Metastasis
Ligands
Phenotype
Therapeutics
Growth
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Song, Bing ; Park, Su Hong ; Zhao, Jonathan C. ; Fong, Kawing W. ; Li, Shangze ; Lee, Yongik ; Yang, Yeqing A. ; Sridhar, Subhasree ; Lu, Xiaodong ; Abdulkadir, Sarki A. ; Vessella, Robert L. ; Morrissey, Colm ; Kuzel, Timothy M. ; Catalona, William ; Yang, Ximing ; Yu, Jindan. / Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 569-582.
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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.",
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Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression. / Song, Bing; Park, Su Hong; Zhao, Jonathan C.; Fong, Kawing W.; Li, Shangze; Lee, Yongik; Yang, Yeqing A.; Sridhar, Subhasree; Lu, Xiaodong; Abdulkadir, Sarki A.; Vessella, Robert L.; Morrissey, Colm; Kuzel, Timothy M.; Catalona, William; Yang, Ximing; Yu, Jindan.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 569-582.

Research output: Contribution to journalArticle

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T1 - Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression

AU - Song, Bing

AU - Park, Su Hong

AU - Zhao, Jonathan C.

AU - Fong, Kawing W.

AU - Li, Shangze

AU - Lee, Yongik

AU - Yang, Yeqing A.

AU - Sridhar, Subhasree

AU - Lu, Xiaodong

AU - Abdulkadir, Sarki A.

AU - Vessella, Robert L.

AU - Morrissey, Colm

AU - Kuzel, Timothy M.

AU - Catalona, William

AU - Yang, Ximing

AU - Yu, Jindan

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N2 - 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.

AB - 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.

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