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

The EMBO Journal
Mark KaliszJorge Ferrer

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.

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Citations

Oct 20, 2020·British Journal of Cancer·Christian SchneeweisGünter Schneider
Aug 1, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rossella TricaricoErica A Golemis
Feb 5, 2021·Nature·Direna Alonso-CurbeloScott W Lowe
Aug 21, 2020·Molecular and Cellular Biology·Nhien TranKai Ge

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Methods Mentioned

BETA
acetylation
PCR
light microscopy
ChIP

Software Mentioned

HOTNET
Deeptools
PlotsOfData
Mutsig
ENRICHR
Illumina
Intogen
Centrimo
bcl2fastq
ggplot2

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