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Título
HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer.
Autor(es)
Kalisz, Mark | Bernardo, Edgar CNIC | Beucher, Anthony | Maestro, Miguel Angel | Del Pozo, Natalia | Millán, Irene | Haeberle, Lena | Schlensog, Martin | Safi, Sami Alexander | Knoefel, Wolfram Trudo | Grau, Vanessa | de Vas, Matías | Shpargel, Karl B | Vaquero, Eva | Magnuson, Terry | Ortega Jimenez, Sagrario CNIO | Esposito, Irene | Real Arribas, Francisco CNIO | Ferrer, Jorge
Fecha de publicación
2020-05-04
Cita
EMBO J . 2020 ;39(9):e102808.
Idioma
Inglés
Tipo de documento
journal article
Resumen
Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.
MESH
Acinar Cells | Animals | Carcinoma, Pancreatic Ductal | Epigenesis, Genetic | Gene Expression Regulation, Neoplastic | Gene Regulatory Networks | Hepatocyte Nuclear Factor 1-alpha | Histone Demethylases | Humans | Mice | Mutation | Organ Specificity | Pancreas | Pancreatic Neoplasms
Versión en línea
DOI
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