Imperial College London
Alternate

ProfessorJorgeFerrer

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Medicine and Genetics
 
 
 
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Contact

 

+44 (0)20 7594 0968j.ferrer

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kalisz:2020:10.15252/embj.2019102808,
author = {Kalisz, M and Bernardo, E and Beucher, A and Maestro, MA and Del, Pozo N and Millán, I and Haeberle, L and Schlensog, M and Safi, SA and Knoefel, WT and Grau, V and de, Vas M and Shpargel, KB and Vaquero, E and Magnuson, T and Ortega, S and Esposito, I and Real, FX and Ferrer, J},
doi = {10.15252/embj.2019102808},
journal = {The EMBO Journal},
title = {HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer},
url = {http://dx.doi.org/10.15252/embj.2019102808},
volume = {39},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Kalisz,M
AU  - Bernardo,E
AU  - Beucher,A
AU  - Maestro,MA
AU  - Del,Pozo N
AU  - Millán,I
AU  - Haeberle,L
AU  - Schlensog,M
AU  - Safi,SA
AU  - Knoefel,WT
AU  - Grau,V
AU  - de,Vas M
AU  - Shpargel,KB
AU  - Vaquero,E
AU  - Magnuson,T
AU  - Ortega,S
AU  - Esposito,I
AU  - Real,FX
AU  - Ferrer,J
DO  - 10.15252/embj.2019102808
PY  - 2020///
SN  - 0261-4189
TI  - HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer
T2  - The EMBO Journal
UR  - http://dx.doi.org/10.15252/embj.2019102808
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32154941
UR  - http://hdl.handle.net/10044/1/79230
VL  - 39
ER  -
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