HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer.

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 (P...

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Detalles Bibliográficos
Autores: Kalisz, Mark, Bernardo, Edgar, 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, Esposito, Irene, Real Arribas, Francisco, Ferrer, Jorge
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18193
Acceso en línea:http://hdl.handle.net/20.500.12105/18193
Access Level:acceso abierto
Palabra clave: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
Descripción
Sumario: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.

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