Journal
EMBO JOURNAL
Volume 39, Issue 9, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019102808
Keywords
HNF1A; KDM6A; non-classical PDAC; pancreas; pancreas differentiation
Categories
Funding
- Wellcome Trust [WT101033]
- Medical Research Council [MR/L02036X/1]
- European Research Council Advanced Grant [789055]
- Ministerio de Ciencia e Innovacion [BFU2014-54284-R, RTI2018-095666-B-I00, SAF2011-29530, SAF2015-70553-R]
- RTICC from Instituto de Salud Carlos III [RD12/0036/0034, RD12/0036/0050]
- Juvenile Diabetes Research Foundation postdoctoral fellowship [3-PDF-2014-192-A-N]
- Fundacio Bancaria La Caixa [100010434, LCF/BQ/ES18/11670009]
- CERCA Programme, Generalitat de Catalunya
- Centro de Excelencia Severo Ochoa [SEV-2012-0208, SEV-2016-0510]
- National Institute for Health Research (NIHR) Imperial Biomedical Research Centre
- Ministerio de Ciencia e Innovacion
- MRC [MR/L02036X/1] Funding Source: UKRI
- European Research Council (ERC) [789055] Funding Source: European Research Council (ERC)
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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 Kras(G12D) 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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