2. Academic Validation
  3. Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer

Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer

  • Gut. 2023 Jun;72(6):1174-1185. doi: 10.1136/gutjnl-2022-328154.
Feda H Hamdan 1 2,  Amro M Abdelrahman # 3,  Ana Patricia Kutschat # 4,  Xin Wang # 4,  Thomas L Ekstrom 5 6,  Nidhi Jalan-Sakrikar 5,  Catherine Wegner Wippel 5,  Negar Taheri 5,  Liezel Tamon 4,  Waltraut Kopp 7 8,  Joana Aggrey-Fynn 5 6,  Aditya V Bhagwate 9,  Roberto Alva-Ruiz 3,  Isaac Lynch 3,  Jennifer Yonkus 3,  Robyn Laura Kosinsky 6,  Jochen Gaedcke 4,  Stephan A Hahn 10,  Jens T Siveke 11 12,  Rondell Graham 13,  Zeynab Najafova 6,  Elisabeth Hessmann 7 8,  Mark J Truty 3,  Steven A Johnsen 14
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA [email protected] [email protected].
  • 2 Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.
  • 3 Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA.
  • 4 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
  • 5 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
  • 6 Robert Bosch Center for Tumor Diseases, Stuttgart, Germany.
  • 7 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany.
  • 8 Clinical Research Unit 5002 (KFO5002), University Medical Center Göttingen, Göttingen, Germany.
  • 9 Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
  • 10 Department of Molecular GI Oncology, Ruhr University Bochum, Bochum, Germany.
  • 11 Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.
  • 12 Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 13 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
  • 14 Robert Bosch Center for Tumor Diseases, Stuttgart, Germany [email protected] [email protected].
  • # Contributed equally.
PMID: 36889906 DOI: 10.1136/gutjnl-2022-328154
Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.

Design: We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC.

Results: iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.

Conclusion: Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

Keywords

chemotherapy; drug resistance; gene regulation; molecular oncology; pancreatic cancer.

Figures
Products