HNF1A recruits UTX to activate a differentiation program that suppresses pancreatic cancer

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 the histone demethylase UTX, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutations phenocopy Utx deficient mutations, and both synergize with Kras G12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic and biochemical studies to show that HNF1A recruits UTX to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates a differentiation program, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. Finally, we identify a subset of non-classical PDAC samples that exhibit the HNF1A/UTX-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A-deficiency promotes PDAC. They also connect the tumor suppressive role of UTX deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition. IntroductionPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality 1 . The incidence of PDAC is rising, yet current chemotherapies are generally ineffective 2 . Genomic analysis of PDAC has identified almost universal driver mutations in KRAS, TP53, SMAD4 and CDKN2A, among a long list of loci that show recurrent somatic mutations and structural variations 3-7 . A small subset of tumors is caused by germ-line mutations in DNA-repair genes 5, 8 , whereas GWAS have identified dozens of common variants that impact PDAC susceptibility 9, 10 . Genetic studies have therefore uncovered leads that promise to define molecular targets for future precision therapies.Up to 18% of PDAC tumors carry mutations in KDM6A 5 , which encodes UTX, a component of the MLL/COMPASS transcriptional co-regulatory complex 11 . UTX catalyzes demethylation of histone H3K27me3, a modification associated with Polycomb-mediated repression [12][13][14] . Most somatic pathogenic UTX mutations are likely to result in a loss of function, and mouse genetic studies have shown that Utx and Kras mutations cooperate to promote PDAC 15, 16 . How UTX is recruited to its genomic targets in pancreatic cells, and the direct mechanisms through which it controls PDAC-relevant genetic programs, is still poorly understood 17 .There is increasing evidence that the transcriptional regulation of differentiated pancreatic exocrine cells is tightly linked to PDAC development and subtype definition [18][19][20][21][22] . Little is known, however, about the underlying molecular underpinnings. We have examined HNF1A, a homeodomain transcriptional regulator of liver, gut, kidney as well as pancreatic acinar and endocrine cells, which has been proposed to act as a candidate pancreatic tumor suppressor [22][23][24][25] . Human heterozygous HNF1A loss of function mu...

Blocking the road to de‐differentiation: HNF 1A/ KDM 6A complex safeguards epithelial integrity in pancreatic cancer

“…To understand the complex interplay of TFs and molecularly altered epigenetic regulators in pancreatic cell identity and plasticity, Kalisz et al () performed elegant in vivo genetic gain and loss‐of‐function experiments to uncover a novel functional link between the TF HNF1A and the histone demethylase KDM6A, thereby the study interconnects for the first time the tumor‐suppressive function of KDM6A to a lineage‐specific TF and shows how both maintain epithelial cell identity in the pancreas.…”

“…In future, it will be also important to discover vulnerabilities and design therapies for HNF1A/KDM6A‐proficient PDAC subtypes. The pioneering work of Kalisz et al () opens new horizons for such attempts by providing the basis for a deeper understanding of the evolution of distinct PDAC subtypes and their associated therapeutic vulnerabilities.…”