Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-β-catenin axis in modulating gemcitabine resistance in pancreatic cancer

  • Cancer Lett. 2024 Nov 28:605:217284. doi: 10.1016/j.canlet.2024.217284.
Dianhui Wei  1 ,  Lili Yuan  1 ,  Xiaoli Xu  1 ,  Chengsi Wu  1 ,  Yiwen Huang  1 ,  Lili Zhang  1 ,  Jilong Zhang  2 ,  Tiantian Jing  3 ,  Yizhen Liu  4 ,  Boshi Wang  5
Affiliations
  • 1. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
  • 2. Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, China. Electronic address: [email protected].
  • 3. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China. Electronic address: [email protected].
  • 4. Department of Medical Oncology, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 39366545 DOI: 10.1016/j.canlet.2024.217284
Abstract

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.

Keywords
Dynamic epigenetic landscape; Gemcitabine resistance; Pancreatic ductal adenocarcinoma (PDAC); Super-enhancer.
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