Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137070 | GEO | 2019/09/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer [ChIP-Seq]

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.

2020-11-30 | GSE162319 | GEO

Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer

2019-09-09 | GSE137071 | GEO

Targeting SOX4/PCK2 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer

Project description:Background: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that SRY-Box transcription factor 4 (SOX4) is upregulated in NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. Methods: To understand the function of SOX4 in the development and progression of NEPC, we detected malignancy characterization after over-expression or knock-down of SOX4 in prostate cancer cells. Xenograft tumors representing NEPC subtypes were analyzed by pathologists. Protein expression profiles were validated in patient tumor tissue. Diagnoses were complemented by transcriptome sequencing and ATAC sequencing of specific cell lines and public clinical datasets. Results: SOX4 expression was significantly elevated in NEPC. Activating SOX4 in non-NEPC cells induced NE transdifferentiation, while silencing it in NEPC cells impeded NEPC progression. SOX4 promote neuroendocrine characteristics by inducing PCK2-mediated metabolism changing. Conclusions: Elevated SOX4 drives NE transdifferentiation in PCa via PCK2-mediated . Altogether, these findings highlight SOX4 as a novel molecule to drive NEPC progression and suggest that it might be a potential therapeutic target for NEPC.

2024-03-31 | GSE261370 | GEO

DPYSL5 is Highly Expressed in treatment-induced Neuroendocrine Prostate Cancer and Promotes Lineage Plasticity via EZH2/PRC2

Project description:Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort with 157 patient samples, including 55 t-NEPC patient samples, shows a high expression of DPYSL5 in t-NEPC patients, and that DPYSL5 correlates with neuroendocrine markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces neuron like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 halts proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a novel driver of t-NEPC progression.

2024-01-02 | GSE151433 | GEO

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 2

Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.

2020-05-29 | PXD012971 | Pride

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 1

2020-05-29 | PXD012970 | Pride

PAX6 promotes neuroendocrine phenotypes of prostate cancer via enhancing MET/STAT5A-mediated chromatin accessibility

Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of prostate cancer characterized by the loss of androgen receptor (AR) signaling and the acquisition of neuroendocrine (NE) characteristics. However, the underlying molecular mechanism, especially related to the drivers or the determinants responsible for NE transdifferentiation, remains unclear. In this study, we compared gene expression profiling of NEPC and non-NEPC specimens and paid a particular attention to those transcriptional factors affecting neural differentiation during development. We identified that Paired box 6 (Pax6) expression was significantly elevated in NEPC and negatively regulated by AR signaling. While knock-down of Pax6 in NEPC cells inhibited NEPC phenotypes, over-expression of Pax6 in non-NEPC cells led to development of NEPC. Mechanistically, loss of AR resulted in an enhanced expression of Pax6, which reprogramed the lineage plasticity of prostate cancer cells to develop NE phenotypes through the c-Met/Stat5a signaling. By performing ATAC-seq, we found that high expression level of Pax6 elicited enhanced chromatin accessibility mainly through attenuation of H4K20me3 that usually causes chromatin silence in cancer cells. Taken together, these findings highlight PAX6 as a novel molecule to drive NEPC progression and suggest that it might serve as a potential target for the management of NEPC.

2024-01-09 | GSE250422 | GEO

Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer [scRNA-seq]

Project description:Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation.

2024-02-09 | GSE225021 | GEO

Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer [RNA-seq_Nov]

2024-02-09 | GSE225017 | GEO

Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer [RNA-seq_Sep]

2024-02-09 | GSE225013 | GEO