Journal Article

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

Catalona, William, Zhao, Jonathan C., Li, Shangze, Park, Su-Hong, Fong, Ka-wing, Sridhar, Subhasree, Lu, Xiaodong, Kuzel, Timothy M., Lee, Yongik, Yu, Jindan, Vessella, Robert L., Yang, Ximing, Yang, Yeqing A., Morrissey, Colm, Abdulkadir, Sarki A., Song, Bing

2019

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Androgens / Animals / Bioinformatics / Biomedical research / Castration / Cell growth / Cell Line, Tumor / Cooperation / Disease resistance / DNA microarrays / Gene expression / Gene Expression Profiling / Genomes / Genomics / Genotype & phenotype / Growth factors / Hepatocyte Nuclear Factor 3-alpha - antagonists & inhibitors / Hepatocyte Nuclear Factor 3-alpha - genetics / Hepatocyte Nuclear Factor 3-alpha - metabolism / Humans / Kinases / Liver cancer / Male / Mesenchyme / Metastases / Metastasis / Mice / Mice, SCID / Motility / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Oligonucleotide Array Sequence Analysis / Phenotypes / Pheochromocytoma cells / Phosphorylation / Plasticity / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - pathology / Proteins / Pyrazoles - pharmacology / Quinolines - pharmacology / Receptor, Transforming Growth Factor-beta Type I - antagonists & inhibitors / Receptor, Transforming Growth Factor-beta Type I - genetics / Receptor, Transforming Growth Factor-beta Type I - metabolism / Signal Transduction / Smad2 protein / Studies / Transforming Growth Factor beta3 - genetics / Transforming Growth Factor beta3 - metabolism / Transforming growth factor-b1 / Tumors / Xenograft Model Antitumor Assays / Xenografts