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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119758 | GEO | 2018/11/01

REPOSITORIES: GEO

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Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression [RNA-Seq]

Project description: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.

2018-11-01 | GSE119757 | GEO

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

Project description: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.

| S-EPMC6355239 | biostudies-literature

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

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

| PRJNA490185 | ENA

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-11-01 | GSE119759 | GEO

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

Project description:Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression [microarray]

| PRJNA490187 | ENA

Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression [RNA-Seq]

Project description:Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression [RNA-Seq]

| PRJNA490188 | ENA

FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [HiChIP]

Project description:The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric differentiation program. Using sequential recombination models, we find that FoxA1/2 are required for demethylation of gastric-defining genes after Nkx2-1 deletion. FoxA1 colocalizes with TET3, an enzyme that mediates DNA demethylation, in NKX2-1-negative tumors. Deletion of Foxa1/2 results in loss of TET3 occupancy at key gastric marker genes, indicating that FoxA1/2 recruit TET3 to lineage-specific sites. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of enhancers and promoters as well as their 3D interactions at gastric target genes following NKX2-1 loss. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming in NKX2-1-negative LUAD. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.

2024-09-11 | GSE247854 | GEO

Nucleation of DNA Repair Factors by FOXA1 Links DNA Demethylation and Transcriptional Pioneering

Project description:We report that the winged helix transcription factor FOXA1 is unexpectedly associated with components of single and double stranded-DNA repair complexes. Biochemical studies and high-throughput approaches validated the hierarchical composition of this FOXA1-nucleated machinery and revealed the dependency on FOXA1 for global targeting of the key repair polymerase POLB. Genome-wide DNA methylomes at single-base resolution demonstrated that FOXA1-DNA repair complex is functionally linked to DNA demethylation in a lineage specific fashion. Loss-of-function studies indicate that a significant portion of FOXA1-bound regions display localized reestablishment of methylation and that the subsets with most consistent hypermethylation are represented by active promoters and enhancers that also exhibit the greatest depletion of POLB following FOXA1 removal. Consistently, forced expression of FOXA1 commits its binding sites to an active DNA demethylation in a POLB dependent manner. Finally, we showed that FOXA1-associated DNA demethylation is tightly coupled with genomic targeting of estrogen receptor and estrogen responsiveness. Together, our results link FOXA1-associated DNA demethylation to its transcriptional pioneering.

2016-06-08 | PXD004271 | Pride

FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [ChIP-seq]

2024-09-11 | GSE247851 | GEO

FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [RNA-Seq]

2024-09-11 | GSE247845 | GEO