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Original article
Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis
  1. Simone Benitz1,2,
  2. Tobias Straub3,
  3. Ujjwal Mukund Mahajan1,
  4. Jurik Mutter1,
  5. Stefan Czemmel4,
  6. Tatjana Unruh5,
  7. Britta Wingerath5,
  8. Sabrina Deubler6,
  9. Lisa Fahr1,
  10. Tao Cheng6,
  11. Sven Nahnsen4,
  12. Philipp Bruns6,
  13. Bo Kong6,
  14. Susanne Raulefs6,
  15. Güralp O Ceyhan6,
  16. Julia Mayerle1,
  17. Katja Steiger7,
  18. Irene Esposito8,
  19. Jörg Kleeff9,
  20. Christoph W Michalski9,
  21. Ivonne Regel1
  1. 1 Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
  2. 2 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3 Bioinformatic Unit, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany
  4. 4 Quantitative Biology Center, University of Tuebingen, Tuebingen, Germany
  5. 5 Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany
  6. 6 Department of Surgery, Technical University Munich, Munich, Germany
  7. 7 Institute of Pathology, Technical University Munich, Munich, Germany
  8. 8 Institute of Pathology, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany
  9. 9 Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
  1. Correspondence to Dr Ivonne Regel; Ivonne.Regel{at}med.uni-muenchen.de

Abstract

Background and aims Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis.

Design With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells.

Results The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype.

Conclusions Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

  • Acinar-to-ductal metaplasia
  • pancreatic cancer
  • epigenetic silencing
  • acinar differentiation genes
  • Ring1b
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Footnotes

  • Funding The work was supported in part by the Deutsche Forschungsgemeinschaft (DFG) RE 3754/2-1.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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