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ETV5 accelerates therapy-induced neuroendocrine prostate cancer development by inducing neural stem-like cell differentiation [ChIP-seq]

ABSTRACT: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype induced by hormone therapy, presenting significant therapeutic challenges due to the lack of effective treatments. In this study, we explored the role of ETV5 in NEPC development. Analysis of multiple prostate cancer datasets revealed significantly elevated ETV5 expression in NEPC compared to other subtypes. ETV5 expression increased progressively under hormone therapy conditions through epigenetic modifications. ETV5 overexpression induced NEPC-like features in LNCaP cells and facilitated their differentiation into NEPC under hormone treatment conditions, both in vitro and in vivo. Our molecular mechanism study identified PBX3 and TLL1 as ETV5 target genes, contributing to castration resistance and stemness induced by ETV5 overexpression. Notably, obeticholic acid, identified as an ETV5 inhibitor in this study, exhibited promising efficacy in suppressing NEPC development. This study highlights ETV5 as a key transcription factor driving NEPC development and underscores its potential as a therapeutic target for this aggressive cancer subtype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271777 | GEO | 2024/09/01

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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ETV5 accelerates therapy-induced neuroendocrine prostate cancer development by inducing neural stem-like cell differentiation [ChIP-seq]

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