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

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• dc.contributor.author Kalisz, Mark
• dc.contributor.author Bernardo, Edgar
• dc.contributor.author Maestro, Miguel Ángel
• dc.contributor.author Grau, Vanessa
• dc.contributor.author Real, Francisco X.
• dc.contributor.author Ferrer, Jorge
• dc.date.accessioned 2020-05-04T07:11:37Z
• dc.date.available 2020-05-04T07:11:37Z
• dc.date.issued 2020
• dc.description.abstract 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.
• dc.description.sponsorship This research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. Work was funded by grants from the Wellcome Trust (WT101033 to J.F.), Medical Research Council (MR/L02036X/1 to J.F.), European Research Council Advanced Grant (789055 to J.F.), Ministerio de Ciencia e Innovación (BFU2014‐54284‐R, RTI2018‐095666‐B‐I00 to J.F., SAF2011‐29530 and SAF2015‐70553‐R to F.X.R.) and RTICC from Instituto de Salud Carlos III (RD12/0036/0034, RD12/0036/0050) to F.X.R. M.K. was supported by a Juvenile Diabetes Research Foundation postdoctoral fellowship (3‐PDF‐2014‐192‐A‐N). I.M. was supported by a Fellowship from Fundació Bancaria La Caixa (ID 100010434) (grant number LCF/BQ/ES18/11670009). Work in CRG was supported by the CERCA Programme, Generalitat de Catalunya, and support from Ministerio de Ciencia e Innovación to the EMBL partnership. Work at CRG and CNIO was supported by Centro de Excelencia Severo Ochoa grants SEV‐2012‐0208, SEV‐2016‐0510.
• dc.format.mimetype application/pdf
• dc.identifier.citation Kalisz M, Bernardo E, Beucher A, Maestro MA, Del Pozo N, Millán I, Haeberle L, Schlensog M, Safi SA, Knoefel WT, Grau V, de Vas M, Shpargel KB, Vaquero E, Magnuson T, Ortega S, Esposito I, Real FX, Ferrer J. HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. EMBO J. 2020; 39(9):e102808. DOI: 10.15252/embj.2019102808
• dc.identifier.doi http://dx.doi.org/10.15252/embj.2019102808
• dc.identifier.issn 0261-4189
• dc.identifier.uri http://hdl.handle.net/10230/44384
• dc.language.iso eng
• dc.publisher EMBO Press
• dc.relation.ispartof EMBO J. 2020; 39(9):e102808
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/789055
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014‐54284‐R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018‐095666‐B‐I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2011‐29530
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015‐70553‐R
• dc.rights © 2020 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword HNF1A
• dc.subject.keyword KDM6A
• dc.subject.keyword Non-classical PDAC
• dc.subject.keyword Pancreas
• dc.subject.keyword Pancreas differentiation
• dc.title HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion