THE NONCANONICAL WNT PATHWAY (FYN/STAT3) ACTIVATED BY YY1 PROMOTES THE NEUROENDOCRINE DIFFERENTIATION OF PROSTATE CANCER CELLS.

IF 2.4 3区医学 Q3 ONCOLOGY

Urologic Oncology-seminars and Original Investigations Pub Date : 2025-03-01 DOI:10.1016/j.urolonc.2024.12.004

Ruij Liu

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引用次数: 0

Abstract

Introduction

A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumors. Here we aimed to uncover the underlying mechanisms by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity.

Methods

Bioinformatics analysis was performed to determine the expression of YY1 in different types of prostate cancer. Aberrant YY1 expression was validated in PCa tissues and cell lines via qRT-PCR. In vitro and in vivo functional experiments were performed to evaluate the role of YY1 in PCa malignancy. RNA sequencing, luciferase reporter assay and ChIP-PCR were used to identify the key downstream genes regulated by YY1. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting.

Results

Using the TCGA and GEO databases, we bioinformatically analyzed the expression of YY1 in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via RT qPCR, western blotting, and IHC. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Bioinformatics analysis revealed aberrant YY1 expression in primary PCa, which was further validated in CRPC and NEPC tissues. Proliferation and metastasis of PCa cells were demonstrated in vitro and in vivo by functional assays. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells through epithelial-mesenchymal transition (EMT) induction and NE differentiation. Mechanically, androgen deprivation therapy (ADT) induces a decrease in ubiquitination of YY1 protein, enhances its stability, and thus enhances the transcriptional activity of FZD8. Castration enhances the binding of FZD8 to Wnt9A and mediates cellular plasticity by activating the noncanonical Wnt (FZD8/FYN/STAT3) pathway.

Conclusions

We identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We hypothesize that an in-depth investigation of the underlying mechanisms of YY1-mediated disease may lead to improved NEPC therapies.

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yy1激活的非典型WNT通路（fyn / stat3）促进前列腺癌细胞的神经内分泌分化。

越来越多的研究表明，阴阳1 （YY1）促进多种肿瘤的发展。在这里，我们旨在揭示YY1介导前列腺癌（NEPC）细胞神经内分泌分化的潜在机制。方法采用生物信息学方法检测YY1在不同类型前列腺癌组织中的表达。通过qRT-PCR验证了YY1在PCa组织和细胞系中的异常表达。通过体外和体内功能实验来评价YY1在前列腺癌恶性肿瘤中的作用。采用RNA测序、荧光素酶报告基因法和ChIP-PCR鉴定YY1调控的下游关键基因。通过Co-IP和western blotting检测蛋白间的泛素化修饰和相互作用。结果利用TCGA和GEO数据库，从生物信息学角度分析了YY1在前列腺癌（PCa）中的表达。通过RT - qPCR、western blotting和IHC验证了YY1在不同PCa组织和细胞系中的异常表达。体内和体外功能实验证实了YY1在PCa中的致癌性。生物信息学分析显示，YY1在原发性PCa中表达异常，并进一步在CRPC和NEPC组织中得到证实。体外和体内功能实验证实了前列腺癌细胞的增殖和转移。进一步的功能分析表明，YY1的异位表达通过上皮-间质转化（epithelial- mesenchal transition， EMT）诱导和NE分化促进了PCa细胞的可塑性。机械上，雄激素剥夺疗法（ADT）诱导YY1蛋白泛素化降低，增强其稳定性，从而增强FZD8的转录活性。去势增强了FZD8与Wnt9A的结合，并通过激活非规范Wnt （FZD8/FYN/STAT3）通路介导细胞可塑性。结论本研究发现YY1是一种新的转录失调因子，在NEPC的进展中起重要作用。我们假设对yy1介导疾病的潜在机制的深入研究可能会导致NEPC治疗的改进。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Urologic Oncology-seminars and Original Investigations 医学-泌尿学与肾脏学

CiteScore

4.80

自引率

3.70%

发文量

297

审稿时长

7.6 weeks

期刊介绍： Urologic Oncology: Seminars and Original Investigations is the official journal of the Society of Urologic Oncology. The journal publishes practical, timely, and relevant clinical and basic science research articles which address any aspect of urologic oncology. Each issue comprises original research, news and topics, survey articles providing short commentaries on other important articles in the urologic oncology literature, and reviews including an in-depth Seminar examining a specific clinical dilemma. The journal periodically publishes supplement issues devoted to areas of current interest to the urologic oncology community. Articles published are of interest to researchers and the clinicians involved in the practice of urologic oncology including urologists, oncologists, and radiologists.