HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2020-05-04
Date Acceptance
2020-02-07
Citation
The EMBO Journal, 2020, 39 (9)
ISSN
0261-4189
Publisher
EMBO Press
Journal / Book Title
The EMBO Journal
Volume
39
Issue
9
Copyright Statement
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32154941
Subjects
HNF1A
KDM6A
non-classical PDAC
pancreas
pancreas differentiation
Publication Status
Published
Coverage Spatial
England
Article Number
ARTN e102808
Date Publish Online
2020-03-10