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

Bing Song; Su Hong Park; Changsheng Zhao; Ka Wing Fong; Shangze Li; Yongik Lee; Yeqing A. Yang; Subhasree Sridhar; Xiaodong Lu; Sarki A. Abdulkadir; Robert L. Vessella; Colm Morrissey; Timothy Michael Kuzel; William Catalona; Ximing Yang; Jindan Yu

doi:10.1172/JCI122367

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

Bing Song, Su Hong Park, Changsheng Zhao, Ka Wing Fong, Shangze Li, Yongik Lee, Yeqing A. Yang, Subhasree Sridhar, Xiaodong Lu, Sarki A. Abdulkadir, Robert L. Vessella, Colm Morrissey, Timothy Michael Kuzel, William Catalona, Ximing Yang, Jindan Yu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

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 language	English (US)
Pages (from-to)	569-582
Number of pages	14
Journal	Journal of Clinical Investigation
Volume	129
Issue number	2
DOIs	https://doi.org/10.1172/JCI122367
State	Published - Feb 1 2019

Funding

We thank Robin Leikin for helpful discussions of the project, Jonathan Anker and Young A. Yoo for help with the mouse work, and Bert Vogelstein for providing SBE-luc plasmid. The compound LY2157299 monohydrate was provided by Eli Lilly and Company. This work was supported in part by NIH grant R01CA172384 (to JY), NIH grant R50CA211271 (to JCZ), NIH prostate SPORE grant P50CA180995 (to JY), and Prostate Cancer Foundation grant 2017CHAL2008 (to JY, JCZ, YL, and CM). Imaging work was performed at the Northwestern University Center for Advanced Microscopy and IHC staining was performed at the Pathology Core Facility, and generously supported by National Cancer Institute grant P30CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. The metastatic CRPC TMA was provided by the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program. We thank the patients and their families, Celestia Higano, Evan Yu, Pete Nelson, Elahe Mostaghel, Heather Cheng, Bruce Montgomery, Mike Schweizer, Paul Lange, Funda Vakar-Lopez, Xiaotun Zhang, Martine Roudier, Lawrence True, and the rapid autopsy teams for their contributions. The rapid autopsy program was supported by the Department of Defense Prostate Cancer Research Program Award (W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1CA163227), and the Institute for Prostate Cancer Research.

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General Medicine

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Song, B., Park, S. H., Zhao, C., Fong, K. W., Li, S., Lee, Y., Yang, Y. A., Sridhar, S., Lu, X., Abdulkadir, S. A., Vessella, R. L., Morrissey, C., Kuzel, T. M., Catalona, W., Yang, X., & Yu, J. (2019). Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression. Journal of Clinical Investigation, 129(2), 569-582. https://doi.org/10.1172/JCI122367

@article{929575e868264e71a3ea1a3c4a1e742d,

title = "Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression",

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.",

author = "Bing Song and Park, {Su Hong} and Changsheng Zhao and Fong, {Ka Wing} and Shangze Li and Yongik Lee and Yang, {Yeqing A.} and Subhasree Sridhar and Xiaodong Lu and Abdulkadir, {Sarki A.} and Vessella, {Robert L.} and Colm Morrissey and Kuzel, {Timothy Michael} and William Catalona and Ximing Yang and Jindan Yu",

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doi = "10.1172/JCI122367",

language = "English (US)",

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Song, B, Park, SH, Zhao, C, Fong, KW, Li, S, Lee, Y, Yang, YA, Sridhar, S, Lu, X, Abdulkadir, SA, Vessella, RL, Morrissey, C, Kuzel, TM, Catalona, W , Yang, X & Yu, J 2019, 'Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression', Journal of Clinical Investigation, vol. 129, no. 2, pp. 569-582. https://doi.org/10.1172/JCI122367

TY - JOUR

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

AU - Song, Bing

AU - Park, Su Hong

AU - Zhao, Changsheng

AU - Fong, Ka Wing

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 Michael

AU - Catalona, William

AU - Yang, Ximing

AU - Yu, Jindan

PY - 2019/2/1

Y1 - 2019/2/1

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

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