Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Guangdong, China.
Gastroenterology. 2024 Jan;166(1):139-154. doi: 10.1053/j.gastro.2023.09.021. Epub 2023 Sep 21.
BACKGROUND & AIMS: 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 remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling 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 tumors 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.
胰腺导管腺癌（PDAC）预后不佳，与胰腺癌症干细胞样细胞（CSCs）的存在有关，这些细胞对当前的化疗方案反应不佳。目前，调节 CSCs 的表观遗传机制了解不足，这阻碍了消除 CSCs 的新策略的发展。
通过针对 142 种表观遗传酶的小分子化合物筛选，我们发现含有溴结构域的蛋白 BRD9 是 BAF 组蛋白重塑复合物的一个组成部分，是通过与 TGFβ/激活素-SMAD2/3 信号通路合作来协调胰腺 CSCs 干性的关键染色质调节剂。
BRD9 的抑制和基因缺失阻止了 CSCs 的自我更新、细胞周期进入 G0 期和侵袭性，并提高了 CSCs 对吉西他滨治疗的敏感性。此外，BRD9 的药理学抑制显著降低了患者来源异种移植小鼠模型中的肿瘤发生，并消除了来自胰腺癌患者的肿瘤中的 CSCs。在机制上，BRD9 的抑制破坏了 CSCs 中干性基因的增强子-启动子环和转录。
总的来说，这些数据表明 BRD9 可作为通过调节 CSC 干性治疗 PDAC 的新治疗靶点。
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