NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation

Isidoro Cobo, Sumit Paliwal, Cristina Bodas, Irene Felipe, Júlia Melià-Alomà, Ariadna Torres, Jaime Martínez-Villarreal, Marina Malumbres, Fernando García, Irene Millán, Natalia Pozo, Joo-Cheol Park, Ray J. MacDonald, Javier Muñoz, Raúl Méndez and Francisco X. Real ()
Additional contact information
Isidoro Cobo: Spanish National Cancer Research Centre-CNIO
Sumit Paliwal: Spanish National Cancer Research Centre-CNIO
Cristina Bodas: Spanish National Cancer Research Centre-CNIO
Irene Felipe: Spanish National Cancer Research Centre-CNIO
Júlia Melià-Alomà: Spanish National Cancer Research Centre-CNIO
Ariadna Torres: Spanish National Cancer Research Centre-CNIO
Jaime Martínez-Villarreal: Spanish National Cancer Research Centre-CNIO
Marina Malumbres: The Barcelona Institute of Science and Technology
Fernando García: Spanish National Cancer Research Centre-CNIO, ProteoRed-Instituto de Salud Carlos III
Irene Millán: Spanish National Cancer Research Centre-CNIO
Natalia Pozo: Spanish National Cancer Research Centre-CNIO
Joo-Cheol Park: Seoul National University
Ray J. MacDonald: University of Texas Southwestern Medical Center
Javier Muñoz: Spanish National Cancer Research Centre-CNIO, ProteoRed-Instituto de Salud Carlos III
Raúl Méndez: The Barcelona Institute of Science and Technology
Francisco X. Real: Spanish National Cancer Research Centre-CNIO

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.

Date: 2023
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DOI: 10.1038/s41467-023-39291-x

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