Jul 2026· Molecular Cancer Research· pp. OF1-OF15· 0 citations
Medicine
TL;DR
It is demonstrated that DNMT3B is required for both the initiation and maintenance of the NEPC phenotype, and its inhibition suppresses NEPC growth and differentiation, highlighting it as a promising therapeutic target for treatment-resistant disease.
Abstract
Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of advanced prostate cancer characterized by poor prognosis and limited treatment options. Enzalutamide, an androgen receptor (AR) pathway inhibitor, is a standard second-line therapy for prostate adenocarcinoma (PrAd). However, enzalutamide resistance (EnzR) promotes not only neuroendocrine differentiation (NED) but also the induction of stemness-associated programs in PrAd cells. We identified the de novo DNA methyltransferase DNMT3B as a stemness-related gene upregulated in EnzR-PrAd cells and found that its expression is further significantly elevated in NEPC compared with PrAd. Our studies reveal that DNMT3B is a critical driver of NEPC development by coordinating the regulation of neuroendocrine and stemness transcriptional networks. Genetic inhibition of DNMT3B suppresses NEPC cell proliferation by impairing cell-cycle progression and triggering apoptosis both in vitro and in vivo. DNMT3B loss altered NED-associated, stemness, and epithelial-associated genes. We further uncover a reciprocal regulatory relationship between DNMT3B and the neuroendocrine transcriptional repressor REST. Using a human prostate cell transformation model that recapitulates NEPC evolution, we demonstrate that DNMT3B is required for both the initiation and maintenance of the NEPC phenotype. Finally, pharmacologic inhibition of DNMT3B with the selective inhibitor Nanaomycin A reduces NEPC tumor growth and suppresses NED and stemness marker expression without apparent acute toxicity in vivo. Implications: DNMT3B drives therapy-induced lineage plasticity in prostate cancer, and its inhibition suppresses NEPC growth and differentiation, highlighting it as a promising therapeutic target for treatment-resistant disease.
Neuroendocrine prostate cancer (NEPC) or small-cell neuroendocrine prostate cancer (SCNPC) is increasingly recognized as a treatment-resistant disease arising among prostate adenocarcinoma (PRAD) patients. It has no effective therapy due to incomplete understanding of the mechanisms underlying treatment-induced cancer cell identity switching. Here, we identified RUNX1 Partner Transcriptional Co-Repressor 1 (RUNX1T1) as a frequently amplified gene in prostate cancer patients, associated with a poorer prognosis. RUNX1T1 is highly expressed and progression-correlated in NEPC and SCNPC. We found that RUNX1T1 is essential for SCNPC survival, as its knockdown induced apoptotic cell death and the acquisition of PRAD-like identity, including alterations in genes involved in cell-cell adhesion and epithelial cell polarity. Functional assays in prostate cancer cell lines revealed that RUNX1T1 regulates genes associated with stemness and the maintenance of neuroendocrine identity in SCNPC. Using our human cell reprogramming assay, which mimics the development of PRAD or SCNPC in vivo, we further demonstrated that RUNX1T1 is required to initiate neuroendocrine differentiation (NED), histological feature changes, and stemness. Its knockout abolished expression of NED and stemness markers and induced loss of SCNPC histological features during SCNPC development. Collectively, these findings establish RUNX1T1 as a critical driver of the cell identity of stem-like SCNPC. Understanding the mechanisms by which RUNX1T1 exerts its versatile regulation of proliferation, stemness, and SCNPC differentiation will in turn pave the way for the discovery of new, specific therapeutic targets to prevent SCNPC progression.
Zi-Qin Wang, H. Jung, Changhyeon Hong et al.· Frontiers in Cell and Develo...· 0 citations
It is demonstrated that INSM1 is consistently upregulated across NEPC patient tumors and experimental models, including both ASCL1⁺ and NEUROD1⁺ molecular subtypes, as revealed by integrated bulk and single-cell transcriptomic analyses.
Chiachen Chen, Siyuan Cheng, Lin Li et al.· bioRxiv· 0 citations
Introduction Neuroendocrine prostate cancer (NEPC) is an aggressive treatment-associated lineage state emerging with potent androgen receptor (AR) pathway inhibition. Although treatment-emergent NEPC is increasingly recognized, the transcriptional consequences of sustained AR suppression remain incompletely defined. It remains unclear to what extent AR-targeted therapies reshape cellular identity and engage neuroendocrine-associated transcriptional programs without full lineage-defining differentiation. Materials and methods Bulk RNA sequencing was performed in AR-dependent LNCaP and castration-resistant C4–2 prostate cancer cells under untreated conditions, androgen deprivation, first-generation AR antagonism with bicalutamide, and second-generation AR pathway inhibition with enzalutamide, using NCI-H660 as a NEPC reference. Transcriptomic organization and pathway-level changes were assessed using principal component analysis, comparative analyses, module score analysis of lineage-associated programs, and Gene Ontology–based functional enrichment. Results In LNCaP cells, AR suppression induced a progressive transcriptomic shift toward the NEPC reference cell line H660, with this trend being most pronounced in enzalutamide-treated cells. Canonical AR target genes (KLK3, TMPRSS2, NKX3-1, and FKBP5) were suppressed, whereas neuroendocrine-associated genes (NCAM1, ENO2, PEG10, and DLL3) showed partial induction. Canonical NEPC markers and lineage-defining transcription factors, including CHGA, INSM1, and SOX2, were not activated. Module score analysis demonstrated selective activation of lineage plasticity–associated programs corresponding to an intermediate Phase 2 state without engagement of canonical neuroendocrine differentiation programs. Gene-wise analyses further showed preferential induction of developmental and plasticity-associated transcriptional programs by enzalutamide compared with bicalutamide. In contrast, C4–2 cells exhibited context-dependent and incomplete neuroendocrine-associated transcriptional changes, consistent with modulation of a pre-existing permissive transcriptional state rather than stable neuroendocrine differentiation. Conclusions Potent AR pathway inhibition does not induce terminal neuroendocrine differentiation in vitro but promotes an adaptive plastic intermediate state characterized by partial activation of neuroendocrine-associated transcriptional programs. These findings suggest that enzalutamide preferentially enhances early lineage plasticity rather than bona fide NEPC differentiation and provide a framework for distinguishing adaptive transcriptional reprogramming from true neuroendocrine lineage conversion in treatment-emergent prostate cancer.
R. Watanabe, M. Chosei, Haruna Arai et al.· Frontiers in Oncology· 0 citations
Lineage plasticity is a major mechanism by which prostate cancer adapts to therapeutic pressure, particularly following sustained inhibition of androgen receptor signaling. A central mediator of this process is BRN2, a POU3F2 neural lineage transcription factor that is normally suppressed in AR-dependent luminal prostate epithelium but becomes aberrantly activated during progression to castration-resistant and neuroendocrine prostate cancer. This review examines how BRN2 connects developmental neurogenesis to therapy-induced tumor reprogramming. We integrate insights from neurodevelopment and direct lineage reprogramming to describe how BRN2 maintains stem-like and neuroendocrine transcriptional states. Mechanistically, we discuss how AR suppression, cooperating oncogenic drivers, epigenetic remodeling, and post-translational modification activate BRN2 and reshape transcriptional networks involving SOX2, Wnt signaling, N-Myc, and EZH2. We also evaluate strategies to target BRN2 and its associated dependencies, including direct inhibition of BRN2 DNA binding and pharmacologic disruption of cooperating epigenetic complexes such as BRD4, EZH2, and LSD1, though EZH2 inhibition may paradoxically promote further neuroendocrine differentiation. We additionally assess BRN2 as a potential circulating biomarker, detectable in extracellular vesicles, though no clinical-grade assay has been validated. This review highlights BRN2 as a key transcriptional regulator of lineage plasticity in prostate cancer, with important implications for overcoming therapy resistance in advanced prostate cancer.
Lineage plasticity, or transdifferentiation, is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Lineage plasticity is characterized by loss of AR signaling and epithelial differentiation, along with activation of stemness-associated pathways, epithelial-mesenchymal transition (EMT), or alternative differentiation programs such as neuroendocrine prostate cancer (NEPC). Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Using multi-omic profiling of TP53/RB1 loss prostate cancer models, we identified alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. Importantly, many pathways activated upon TP53/RB1 loss could be blocked through BET bromodomain inhibition. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with restraining lineage plasticity. Combined BET bromodomain and DNA methyltransferase (DNMT) inhibition was more effective than single agent treatment in suppressing growth of TP53/RB1 loss models exhibiting a stem-like or NEPC program. This was partly explained by abrogation of discrete lineage plasticity pathways modulated by each agent. Altogether, our work suggests combined BET bromodomain and DNMT inhibition is a promising therapeutic approach for prostate tumors exhibiting lineage plasticity.
W. Storck, Diana Flores, A. Kumaraswamy et al.· JCI Insight· 0 citations
Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.
Chen-Lin Yu, Chia-Liang Lin, Hsiang-Lin Lee et al.· Cell Death Discovery· 0 citations
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