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RUNX1T1 roles in neuroendocrine prostate cancer

ABSTRACT: Prostate cancer is the second most common cancer in men worldwide, affecting large proportions of the population. Although indolent as prostate adenocarcinoma (PRAD) at first, the standard hormonal therapy inevitably induced metastatic and lethal neuroendocrine prostate cancer (NEPC) or small cell neuroendocrine prostate cancer (SCNPC), which currently has no specific and standard therapies due to a lack of understanding of the underlying biochemical mechanisms of progression. In this study, we identified RUNX1 Partner Transcriptional Co-Repressor 1 (RUNX1T1) as a frequently amplified, AR-regulated gene in prostate cancer, with its high expression associated with NEPC progression. Our analysis of hallmarks and gene ontology based on RNA-seq of NEPC suggests that RUNX1T1 knockdown induced cell-cell adhesion and epithelial cell polarity, features related to a PRAD identity. Our functional analysis, based on gain- and loss-of-function in vitro/in vivo cell line models, revealed that RUNX1T1 is required for NEPC survival, stemness, and maintenance of SCNPC identity. Using our human cell reprogramming assay to model aggressive SCNPC, we further demonstrated that RUNX1T1 is required to maintain the identity of stem-like SCNPC, as its knockout abolished expression of NE and stemness markers and induced loss of SCNPC histology. Collectively, these findings establish RUNX1T1 as a critical regulator of hormonal therapy-induced neuroendocrine differentiation and histological transformation of SCNPC. Furthermore, understanding the mechanisms by which RUNX1T1 exerts its versatile regulation of proliferation, stemness, and SCNPC differentiation will pave the way for the discovery of new, specific therapeutic targets to prevent NEPC or SCNPC progression at an early stage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330171 | GEO | 2026/09/16

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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RUNX1T1 roles in neuroendocrine prostate cancer

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