Premium
HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer
Author(s) -
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 Sagrario,
Esposito Irene,
Real Francisco X,
Ferrer Jorge
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102808
Subject(s) - biology , hnf1a , pancreatic cancer , cancer research , cancer , cell , microbiology and biotechnology , genetics , gene
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.