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DNMT3B drives neuroendocrine lineage plasticity and aggressive progression in prostate cancer

ABSTRACT: Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-resistant subtype of prostate cancer characterized by poor prognosis and limited therapeutic options. In this study, we identify de novo DNA methyltransferase 3B (DNMT3B) as a critical driver of NEPC growth and neuroendocrine differentiation. We demonstrate that DNMT3B expression is significantly upregulated during prostate cancer progression and is essential for NEPC cell proliferation, as its genetic inhibition via CRISPR-Cas9 and inducible shRNA systems impairs tumor growth and promotes apoptosis both in vitro and in vivo. Transcriptomic profiling reveals that DNMT3B loss disrupts cell cycle regulation and suppresses neuroendocrine lineage programs by downregulating key transcription factors such as FOXA2, NEUROD1, SOX2, and INSM1. Moreover, DNMT3B is required for both the initiation and maintenance of NEPC in a human genetically engineered prostate cancer model. Pharmacological inhibition of DNMT3B with Nanaomycin A selectively suppresses NEPC tumor growth and attenuates neuroendocrine marker expression without causing systemic toxicity. These findings establish DNMT3B as a central regulator of NEPC and support its potential as a therapeutic target for this lethal cancer subtype

ORGANISM(S): Homo sapiens

PROVIDER: GSE302864 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, exhibiting rapid progression and is unresponsive to hormone therapy. Reliable prognostic assays and more effective treatments are critically required. However, the research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we successfully developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation from prostate adenocarcinoma. By comparing gene expression profiles of the parental adenocarcinoma line (LTL331) and the NEPC subline (LTL331R), we identified DEK, a gene not previously reported in prostate cancer, as a potential biomarker and target for NEPC. Methods: DEK protein expression in patient tissue-derived xenograft models and clinical samples was assessed by immunohistochemistry. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis. Results: Elevated DEK protein expression was observed in all clinical NEPC cases, which is distinct from their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Increased DEK expression is an independent clinical risk factor and is associated with shorter disease free survival in hormonal naïve prostate cancer patients. Reduction of DEK expression in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. Conclusions: The results suggest that DEK may play an important role in the progression of prostate cancer, especially NEPC and provide a potential biomarker to aid risk stratification of prostate cancer and a novel therapeutic target for treating NEPC. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis.

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DNMT3B drives neuroendocrine lineage plasticity and aggressive progression in prostate cancer

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