ArticleCell death discovery2024
Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST.
Article in Cell death discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Article
- Tumor-Associated Macrophage Exosomal miR-142-5p Drives Prostate Cancer Neuroendocrine Differentiation via RERG/Ras/ERK Axis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- When PSMA is not enough: the diagnostic blind spots of PSMA PET/CT and the added value of [¹⁸F]FDG in high-risk prostate cancer: dual-tracer cohort study.Cancer imaging : the official publication of the International Cancer Imaging Society · 2026Article
- c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.Cell death & disease · 2026Article
- Genetic and epigenetic mechanisms underlying treatment-induced neuroendocrine prostate cancer.Journal of the National Cancer Center · 2026Review
- Advances in understanding the tumor microenvironment of neuroendocrine prostate cancer.Frontiers in oncology · 2026Review
- Molecular mechanisms and classification of castration-resistant prostate cancer: Insights into androgen receptor, cancer stem cells, and neuroendocrine features.Current urology · 2026Article
- The castration-resistant prostate cancer-associated SNP rs11067228 facilitates neuroendocrine differentiation through an enhancer-mediated chromatin interaction with SRRM4.International journal of biological sciences · 2026Article
- Cancer cell plasticity and therapeutic resistance: mechanisms, crosstalk, and translational perspectives.Hereditas · 2025Review
- Tumor-intrinsic regulators of the immune-cold microenvironment of prostate cancer.Trends in endocrinology and metabolism: TEM · 2025Review
- Article
- Therapeutic Exploitation of Neuroendocrine Transdifferentiation Drivers in Prostate Cancer.Cells · 2024Review
- Regulation of Molecular Biomarkers Associated with the Progression of Prostate Cancer.International journal of molecular sciences · 2024Review
- Promising therapy for neuroendocrine prostate cancer: current status and future directions.Therapeutic advances in medical oncology · 2024Review
- Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression.Open life sciences · 2024Article
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Authors and funding
11 authors.
Funding
Abstract
Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2's repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.