Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 2, Pages 569-582Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI122367
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Funding
- NIH grant [R01CA172384, R50CA211271]
- NIH prostate SPORE grant [P50CA180995]
- Prostate Cancer Foundation [2017CHAL2008]
- National Cancer Institute [P30CA060553]
- Department of Defense Prostate Cancer Research Program Award [W81XWH-14-2-0183]
- Pacific Northwest Prostate Cancer SPORE [P50CA97186]
- PO1 NIH grant [PO1CA163227]
- Institute for Prostate Cancer Research
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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-beta 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-beta signaling, EMT, and cell motility, which is effectively blocked by the TGF-beta receptor I inhibitor galunisertib (LY2157299). Tissue microarray analysis confirmed reduced levels of FOXA1 protein and a concordant increase in TGF-beta 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-beta signaling, and supports a novel therapeutic strategy to control lineage switching and potentially extend clinical response to antiandrogen therapies.
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