2026-07-22T20:05:48Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/181932024-11-29T20:45:50Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Kalisz, Mark
author
Bernardo, Edgar
author
Beucher, Anthony
author
Maestro, Miguel Angel
author
Del Pozo, Natalia
author
Millán, Irene
author
Haeberle, Lena
author
Schlensog, Martin
author
Safi, Sami Alexander
author
Knoefel, Wolfram Trudo
author
Grau, Vanessa
author
de Vas, Matías
author
Shpargel, Karl B
author
Vaquero, Eva
author
Magnuson, Terry
author
Ortega Jimenez, Sagrario
author
Esposito, Irene
author
Real Arribas, Francisco
author
Ferrer, Jorge
funder
Wellcome Trust
funder
UK Research and Innovation
funder
Medical Research Council (Reino Unido)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Instituto de Salud Carlos III
funder
Juvenile Diabetes Research Foundation
funder
Fundación La Caixa
funder
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
funder
NIHR - Imperial Biomedical Research Centre (Reino Unido)
2024-02-14T09:49:33Z
2024-02-14T09:49:33Z
2020-05-04
EMBO J . 2020 ;39(9):e102808.
10.15252/embj.2019102808
1460-2075
The EMBO journal
32154941
http://hdl.handle.net/20.500.12105/18193
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.
eng
HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer.
journal article
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