SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303171 | GEO | 2025/07/25
REPOSITORIES: GEO
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Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
2019-09-09 | GSE137071 | GEO
Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
2019-09-09 | GSE137070 | GEO
Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
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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.
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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.
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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.
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Project description:Lineage plasticity in prostate cancer is now recognized as a critical determinant of lethality. It represents a continuum, ranging from AR activity-low tumors to AR-null tumors that do not express a neuroendocrine prostate cancer (NEPC) program—referred to as double-negative prostate cancer (DNPC)—and fully AR-null NEPC tumors. Despite its importance, factors upregulated early in the process of lineage plasticity have yet to be identified. Identifying such factors is crucial for detecting tumors that are undergoing lineage plasticity or are at risk of developing it. Through integrative genomic analysis of metastatic castration-resistant prostate cancer patient tumors, patient-derived xenografts, and cell models, we found that PROX1 is upregulated early in the lineage plasticity continuum, particularly in AR activity-low tumors, and progressively increases in DNPC and NEPC tumors. Our functional studies demonstrated that PROX1 plays a pivotal role in NEPC, as its knockdown (KD) using lentiviral shRNA reduces the neuroendocrine phenotype, decreases cell proliferation, and increases apoptosis. In this dataset, we provide RNA-seq data from PROX1 KD in NEPC cells (NCI-H660), revealing key pathways altered by PROX1 suppression. These findings suggest that PROX1 is a promising target in NEPC treatment.
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