Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression
Bing Song, Su-Hong Park, Jonathan C. Zhao, Ka-wing 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
Bing Song, Su-Hong Park, Jonathan C. Zhao, Ka-wing 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
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Research Article Genetics Oncology

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.

Authors

Bing Song, Su-Hong Park, Jonathan C. Zhao, Ka-wing 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

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Figure 1

FOXA1 suppresses TGFB3 gene transcription.

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FOXA1 suppresses TGFB3 gene transcription. (A) Heat map of differentiall...
(A) Heat map of differentially expressed genes in LNCaP cells infected with control (shCtr) versus shFOXA1 profiled by RNA-seq. FOXA1-regulated genes were selected by DESeq2 with at least 2-fold changes in expression (RPKM) and Benjamini-Hochberg adjusted P values less than 0.01. Each row corresponds to one gene and each column one sample. Data shown are log2 RPKM values. The 4 bar plots on the right indicate FOXA1 ChIP-seq binding within 5 kb, 10 kb, 30 kb or 50 kb of transcription start site (TSS). (B) Volcano plot showing differentially expressed genes between shCtrl and shFOXA1 LNCaP cells. The x axis represents log2 (shFOXA1/shCtrl) for each gene, and the y axis shows statistical significance. Orange dots indicate differentially expressed genes (adjusted P ≤ 0.001); light blue dots are genes with insignificant changes; gray dots are genes with less than 2-fold changes. TGFB3 gene is highlighted by a green circle. (C and D) TGFB3 gene expressions (C) and TGF-β3 protein levels (D) are upregulated upon FOXA1 knockdown. LNCaP, VCaP and C4-2B cells were infected with shCtr or shFOXA1 lentivirus followed by puromycin selection, and then analyzed by qRT-PCR and Western blots (n = 3, *P < 0.05). (E) FOXA1-WT overexpression rescues FOXA1 loss induced TGFB3 gene expression. LNCaP cells were infected with either shCtr or shFOXA1-knockdown lentivirus with or without FOXA1-WT reexpressing lentivirus and harvested for qRT-PCR analysis (n = 3, *P < 0.05).