RNA 结合基序蛋白 39 (RBM39) 在多种癌症类型中既充当 RNA 结合蛋白又充当剪接因子。然而，RBM39 在胆管癌 (CCA) 中的功能仍不清楚。在本研究中，我们旨在研究RBM39在CCA中的作用并探索其作为治疗靶点的潜力。通过分析人类CCA肿瘤标本来研究RBM39在CCA中的表达。在体外和体内进行 CRISPR/Cas9 或 shRNA 介导的 RBM39 耗竭，以记录 RBM39 在 CCA 中的致癌作用。 RBM39 抑制剂 Indisulam 与 EZH2 降解剂 MS177 联合使用的抗肿瘤作用在体外和体内进行了评估。RBM39 在人类 CCA 组织中显着增加，与 CCA 患者的不良预后相关。通过 CRISPR/Cas9 或 shRNA 消除 RBM39 可抑制体外 CCA 细胞增殖，并阻止小鼠中 CCA 的发展和肿瘤生长。从机制上讲，我们的结果表明，RBM39 的缺失通过破坏 EZH2 的 mRNA 剪接来抑制 EZH2 的表达。 RBM39 调节的 EZH2 控制 WNT7B/β-连环蛋白活性。 RBM39（与 Indisulam）和 EZH2（与 MS177）的药理学共同靶向可在体外和体内产生协同抗肿瘤作用。这项研究公开了一种新的 RBM39-EZH2-β-catenin 信号轴，该信号轴对于 CCA 生长至关重要。我们的研究结果表明，同时抑制 RBM39 和 EZH2 为 CCA 治疗提供了一种有前景的治疗策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

The RNA-binding motif protein 39 (RBM39) functions as both an RNA-binding protein and a splicing factor in a variety of cancer types. However, the function of RBM39 in cholangiocarcinoma (CCA) remains undefined. In this study, we aimed to investigate the role of RBM39 in CCA and explore its potential as a therapeutic target.The expression of RBM39 in CCA was investigated by analyzing human CCA tumor specimens. CRISPR/Cas9 or shRNA-mediated depletion of RBM39 was performed in vitro and in vivo to document the oncogenic role of RBM39 in CCA. The anti-tumor effect of the RBM39 inhibitor, Indisulam, in combination with the EZH2 degrader MS177 was assessed in vitro and in vivo.RBM39 is significantly increased in human CCA tissues and associated with a poor prognosis in patients with CCA. Depletion of RBM39 by CRISPR/Cas9 or shRNA inhibited CCA cell proliferation in vitro and prevented CCA development and tumor growth in mice. Mechanistically, our results showed that depletion of RBM39 suppressed EZH2 expression via disrupting its mRNA splicing. RBM39-regulated EZH2 controls WNT7B/β-catenin activity. Pharmacological co-targeting of RBM39 (with Indisulam) and EZH2 (with MS177) resulted in a synergistic antitumor effect, both in vitro and in vivo.This study discloses a novel RBM39-EZH2-β-catenin signaling axis that is crucial for CCA growth. Our findings suggest that simultaneous inhibition of RBM39 and EZH2 presents a promising therapeutic strategy for CCA treatment.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.