Histone Deacetylase 3 as An Orchestrator of Pancre-atic Acinar Cell Regeneration and Neoplasia

Background: Introduction 95% of pancreatic cancer originates from exocrine acinar and ductal cells. In response to insults, such as inflammation during pancreatitis, acinar cells are able to regenerate, by undergoing transient acinar-to-ductal metapla-sia (ADM). However, this cellular plasticity can also facilitate pancreatic neoplasia and constitutes a risk factor for pancreatic cancer (PDAC). Objective Our objective was to uncover new regulators of pancreatic regeneration and neoplasia. We previ-ously highlighted roles of HDAC epigenetic modifiers in pan-creas development and disease. Here, we focused on Histone deacetylase 3 (Hdac3), providing its enzymatic activity to the NCoR/SMRT transcriptional complex, and can act both as an activator and repressor of transcription.Materials and Methods: We conditionally inactivated Hdac3 in mice, either in pancreatic progenitors using Pdx1-Cre; Hdac3fl/ fl mice or in pancreatic acinar cells with Ptf1a-CreER; Hdac3fl/fl mice. Pancreatitis was induced using cerulein treatment.Results: We found that lack of Hdac3 in pancreatic progenitors leads to a strong pancreatic hypoplasia and early lethality in mice with loss of acinar cells and ADM. While Hdac3 inactiva-tion in pancreatic acinar cells perinatally and in adults has no effect at homeostasis, it severely impairs pancreatic regenera-tion and induces neoplasia in the context of acute pancreatitis. Conclusion: Our results show that Hdac3 is specifically in-volved in acinar cell regeneration, recapitulating an embryonic program. Elucidating the specialized functions of HDAC3 in acinar regeneration and neoplasia initiation is crucial to exploit this epigenetic factor as a biomarker and identify new regula-tors and therapeutic targets of pancreatitis and pancreatic can-cer drivers.

Keywords:

Regeneration , Acinar Cells , HDAC3