FOXA2/AP-1 drives prostate cancer lineage plasticity [PDX ChIP-seq]
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ABSTRACT:
PROVIDER: PRJNA972716 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:FOXA (Forkhead Box Protein A) family proteins function as pioneer transcription factors by loosening the compact chromatin structure and facilitating access for other transcription factors. The role of FOXA1 has been intensively studied in normal prostate epithelial cells and the adenocarcinoma subtype of prostate cancer (PCa) where it acts as a critical pioneer factor for the chromatin binding of androgen receptor (AR). Recent studies have indicated the emergence of FOXA2 as an adaptive response to AR signaling inhibition, particularly in prostate tumors that have undergone lineage reprogramming to a neuroendocrine PCa subtype. However, the molecular basis for this transition from FOXA1 to FOXA2 and its role in regulating the development of PCa lineage plasticity remains unclear. In this study, we show that FOXA2 binds to distinct chromatin regions in multiple AR-null PCa models with different molecular subtypes and that its binding is dependent on an epigenetic factor, LSD1. More importantly, we demonstrate that FOXA2 can function as a major pioneer factor of JUN and govern the chromatin binding of AP-1 complex in PCa exhibiting lineage plasticity. Mechanistically, differential reprogramming of JUN activates lineage-specific super-enhancers that may promote PCa progression by enhancing cell state transitions to multiple lineages. Overall, our study reveals a pivotal function of the LSD1-FOXA2 axis in rewiring AP-1 to induce differential transcriptional reprogramming required for PCa lineage plasticity.
2024-04-22 | GSE232553 | GEO
Project description:FOXA2/AP-1 drives prostate cancer lineage plasticity
| PRJNA972713 | ENA
Project description:FOXA (Forkhead Box Protein A) family proteins function as pioneer transcription factors by loosening the compact chromatin structure and facilitating access for other transcription factors. The role of FOXA1 has been intensively studied in normal prostate epithelial cells and the adenocarcinoma subtype of prostate cancer (PCa) where it acts as a critical pioneer factor for the chromatin binding of androgen receptor (AR). Recent studies have indicated the emergence of FOXA2 as an adaptive response to AR signaling inhibition, particularly in prostate tumors that have undergone lineage reprogramming to a neuroendocrine PCa subtype. However, the molecular basis for this transition from FOXA1 to FOXA2 and its role in regulating the development of PCa lineage plasticity remains unclear. In this study, we show that FOXA2 binds to distinct chromatin regions in multiple AR-null PCa models with different molecular subtypes and that its binding is dependent on an epigenetic factor, LSD1. More importantly, we demonstrate that FOXA2 can function as a major pioneer factor of JUN and govern the chromatin binding of AP-1 complex in PCa exhibiting lineage plasticity. Mechanistically, differential reprogramming of JUN activates lineage-specific super-enhancers that may promote PCa progression by enhancing cell state transitions to multiple lineages. Overall, our study reveals a pivotal function of the LSD1-FOXA2 axis in rewiring AP-1 to induce differential transcriptional reprogramming required for PCa lineage plasticity.
2024-04-22 | GSE232552 | GEO
Project description:FOXA (Forkhead Box Protein A) family proteins function as pioneer transcription factors by loosening the compact chromatin structure and facilitating access for other transcription factors. The role of FOXA1 has been intensively studied in normal prostate epithelial cells and the adenocarcinoma subtype of prostate cancer (PCa) where it acts as a critical pioneer factor for the chromatin binding of androgen receptor (AR). Recent studies have indicated the emergence of FOXA2 as an adaptive response to AR signaling inhibition, particularly in prostate tumors that have undergone lineage reprogramming to a neuroendocrine PCa subtype. However, the molecular basis for this transition from FOXA1 to FOXA2 and its role in regulating the development of PCa lineage plasticity remains unclear. In this study, we show that FOXA2 binds to distinct chromatin regions in multiple AR-null PCa models with different molecular subtypes and that its binding is dependent on an epigenetic factor, LSD1. More importantly, we demonstrate that FOXA2 can function as a major pioneer factor of JUN and govern the chromatin binding of AP-1 complex in PCa exhibiting lineage plasticity. Mechanistically, differential reprogramming of JUN activates lineage-specific super-enhancers that may promote PCa progression by enhancing cell state transitions to multiple lineages. Overall, our study reveals a pivotal function of the LSD1-FOXA2 axis in rewiring AP-1 to induce differential transcriptional reprogramming required for PCa lineage plasticity.
2024-04-22 | GSE232554 | GEO
Project description:FOXA2/AP-1 drives prostate cancer lineage plasticity [RNA-seq]
| PRJNA972718 | ENA
Project description:FOXA2/AP-1 drives prostate cancer lineage plasticity [ChIP-seq]
| PRJNA972717 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-04-22 | GSE232555 | GEO
Project description:For FLAG pull-down, protein extracts of cells stably expressing FLAG-tagged FOXA2 were incubated with FLAG-conjugated beads. To perform mass spectrometry analysis, we used at least 6 x 108 cells to map post-translational modification sites through Thermo EASY-nLC 1200 at the Proteomics Core of University of Massachusetts Boston
2024-05-15 | MSV000094773 | MassIVE
Project description:Emerging evidence suggests that the epigenetic state, including the DNA methylation, chromatin accessibility and histone modification, is substantially remodeled, leading to transcriptional reprogramming during the transformation of castration resistant adenocarcinoma (CRPC-Adeno) to neuroendocrine (CRPC-NE) lineage and LUAD to LUAD-SCLC lineage . However, the underlying mechanism is largely unknown. Here, we found FOXA2 transdifferentiates prostate adenocarcinoma away from an AR+/AR gene signature positive (AR+/ARS+) luminal cell lineage to an embryonic and neuroendocrine-lineage by inducing a population of AR+/ARS- transient cells through NKX2-1. Mechanistically, as a pioneer factor, FOXA2 primes NE lineage enhancers by inducing regional chromatin accessibility and DNA demethylation at early stage of transformation. Whereas, once the expression of NKX2-1 is induced by FOXA2, FOXA2 interacts with NKX2-1, mediates gene promoter and enhancer looping and cooperatively recruits P300/CBP complex to NE lineage enhancers, thereby activates NE lineage gene transcription. Interestingly, similar mechanism is also observed in SCLC cancer, suggesting FOXA2 and NKX2-1 are general regulators orchestrating the epigenetic landscape of NE lineage cancer. Finally, therapeutic targeting P300/CBP with CCS1477 which is in clinical trial for lethal PCa significantly impairs NEPC tumor growth.
2025-06-06 | GSE239276 | GEO
Project description:Emerging evidence suggests that the epigenetic state, including the DNA methylation, chromatin accessibility and histone modification, is substantially remodeled, leading to transcriptional reprogramming during the transformation of castration resistant adenocarcinoma (CRPC-Adeno) to neuroendocrine (CRPC-NE) lineage and LUAD to LUAD-SCLC lineage . However, the underlying mechanism is largely unknown. Here, we found FOXA2 transdifferentiates prostate adenocarcinoma away from an AR+/AR gene signature positive (AR+/ARS+) luminal cell lineage to an embryonic and neuroendocrine-lineage by inducing a population of AR+/ARS- transient cells through NKX2-1. Mechanistically, as a pioneer factor, FOXA2 primes NE lineage enhancers by inducing regional chromatin accessibility and DNA demethylation at early stage of transformation. Whereas, once the expression of NKX2-1 is induced by FOXA2, FOXA2 interacts with NKX2-1, mediates gene promoter and enhancer looping and cooperatively recruits P300/CBP complex to NE lineage enhancers, thereby activates NE lineage gene transcription. Interestingly, similar mechanism is also observed in SCLC cancer, suggesting FOXA2 and NKX2-1 are general regulators orchestrating the epigenetic landscape of NE lineage cancer. Finally, therapeutic targeting P300/CBP with CCS1477 which is in clinical trial for lethal PCa significantly impairs NEPC tumor growth.
2025-06-06 | GSE289790 | GEO