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

Mark Kalisz,Anthony Beucher,Miguel Angel Maestro,Terry Magnuson,Irene Esposito,Eva Vaquero,Jorge Ferrer,Sami Alexander Safi,Francisco X Real,Martin Schlensog,Irene Millán,Natalia Del Pozo,Matías De Vas,Wolfram Trudo Knoefel,Lena Haeberle,Sagrario Ortega,Karl B Shpargel,Edgar Bernardo,Vanessa Grau

doi:10.15252/embj.2019102808

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 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.

Highlights

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood
Hnf1apKO;KrasG12D mice showed no lesions at 7 days of age (Fig 1C and D), yet by weaning they had already developed focal acinar-to-ductal metaplasia (ADM) and desmoplastic reactions, which became more prominent as the mice aged (Fig 1F, G, I and J and data not shown)
Eight-weekold Hnf1apKO;KrasG12D mice showed non-invasive atypical tubular complexes, higher-grade PanINs with luminal budding, desmoplastic reaction, and foci of spindle cell proliferation, some of which showed incipient infiltrative growth (Fig 1L, M, O and P). These findings indicate that pancreatic Hnf1a deficiency cooperates with Kras to promote sarcomatoid forms of pancreatic ductal adenocarcinoma (PDAC)

Summary

Introduction

Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. We identify a subset of nonclassical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They connect the tumorsuppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition. We combine mouse genetics, transcriptomics, and genome binding studies to show that HNF1A is a major determinant for the recruitment of KDM6A to its genomic targets in acinar cells This remodels the enhancer landscape of acinar cells and activates a broad epithelial cell transcriptional program that inhibits tumor suppressor pathways. We define a subset of human tumors that exhibit HNF1A/KDM6Adeficient transcriptional programs These findings, provide a molecular mechanism that connects the tumor-suppressive functions of KDM6A and pancreatic differentiation transcription factors

Results

40 Most Down-Regulated Genes in Kdm6apKO

Discussion

Materials and Methods

Statistical methods