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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Castration-resistant prostate cancer (CRPC) is a fatal stage of prostate cancer.
• CRPC develops resistance to therapies like enzalutamide via lineage plasticity, including epithelial-mesenchymal transition (EMT).
• FOXA1 is a key transcription factor for maintaining epithelial cell identity.

Purpose of the Study:

• To investigate the role of FOXA1 in CRPC progression and resistance to antiandrogen therapy.
• To elucidate the molecular mechanisms by which FOXA1 loss drives lineage plasticity.
• To evaluate the therapeutic potential of targeting the identified pathway in CRPC.

Main Methods:

• Studied the effect of FOXA1 loss on gene expression, focusing on transforming growth factor beta 3 (TGFB3).
• Investigated FOXA1's direct binding to the TGFB3 enhancer region using genomic occupancy assays.
• Utilized TGF-β receptor I inhibitor galunisertib (LY2157299) in vitro and in vivo models of CRPC.
• Analyzed tissue microarrays from primary and CRPC tumors to assess FOXA1 and TGF-β signaling levels.

Main Results:

• FOXA1 loss significantly upregulates TGFB3 expression by relieving its direct transcriptional inhibition.
• Downregulation of FOXA1 promotes TGF-β signaling, EMT, and cell motility, which are blocked by galunisertib.
• CRPC tissues show reduced FOXA1 and increased TGF-β signaling (SMAD2 phosphorylation) compared to primary tumors.
• Combined treatment with galunisertib and enzalutamide synergistically inhibited CRPC cell invasion, tumor growth, and metastasis.

Conclusions:

• FOXA1 is a critical regulator of lineage plasticity in CRPC, partly through TGF-β signaling.
• Targeting TGF-β signaling with galunisertib can overcome enzalutamide resistance.
• This combinatorial approach offers a promising strategy to control lineage switching and improve antiandrogen therapy efficacy.