化疗耐药仍然是胰腺导管腺癌（PDAC）治疗中的一个巨大挑战，需要全面探索潜在的分子机制。这项工作旨在研究 PDAC 吉西他滨耐药性发展过程中的动态表观遗传景观，特别关注超级增强子及其调节作用。我们采用成熟的吉西他滨耐药 (Gem-R) PDAC 细胞系对表观基因组、增强子连接组和转录组进行高通量分析。我们的研究结果揭示了从吉西他滨敏感到耐药的 PDAC 细胞转变过程中表观遗传景观和基因组结构发生了显着变化。值得注意的是，我们观察到超级增强子的激活状态具有很大的可塑性，其中相当大比例的顺式元件在化疗耐药细胞中失活。此外，我们确定 NDRG1 超级增强子 (NDRG1-SE) 是功能丧失的超级增强子中吉西他滨耐药的关键调节因子。 NDRG1-SE 失活诱导 WNT/β-连环蛋白信号激活，从而赋予吉西他滨耐药性。这项工作强调了 NDRG1 超级增强子失活驱动的 β-catenin 通路激活是获得吉西他滨耐药性的关键调节因子。这些发现增进了我们对 PDAC 生物学的理解，并为开发针对这种恶性疾病化疗耐药性的有效治疗方法提供了宝贵的见解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.Copyright © 2024 Elsevier B.V. All rights reserved.