胰管腺癌（PDAC）的低预后与胰腺癌干细胞（CSCs）的存在有关，这些细胞对目前的化疗方案反应不佳。目前对调控CSCs的表观遗传机制尚不完全了解，这妨碍了开发消除CSCs的新策略。通过针对142种表观遗传酶进行小分子化合物筛选，我们发现，包含bromodomain的蛋白质BRD9是一个关键的染色质调控因子，能够通过与TGFβ/Activin-SMAD2/3信号通路合作来协调胰腺CSCs的干性。抑制和基因消除BRD9可以阻断CSCs的自我更新、细胞周期进入G0期以及侵袭性，并提高CSCs对Gemcitabine的敏感性。此外，药物抑制BRD9显著减少了来源于胰腺癌患者的异种移植小鼠模型的肿瘤发生，并消除了肿瘤中的CSCs。在机制上，BRD9的抑制打乱了CSCs中增强子-启动子环结和干性基因的转录。总体而言，这些数据表明BRD9是PDAC治疗的一个新的治疗靶点，可以通过调节CSCs的干性来发挥作用。版权所有©2023 AGA Institute. Elsevier Inc.发表，保留所有权利。

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood which hampers the development of novel strategies for eliminating CSCs.By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway.Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to Gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.