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 Lysinespecific 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 nonclassical 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 tumorsuppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition.
This study shows how Hnf1b inactivation in pancreatic ductal cells leads to chronic pancreatitis, neoplasia, and potentiates pancreatic intraepithelial neoplasia formation. This shows a cause of pancreatitis and identifies Hnf1b as a potential tumor suppressor for pancreatic cancer.
While insulin has mitogenic effects in many cell types, its effects on β cells remain elusive. In this issue of Cell Metabolism, Szabat et al. (2015) genetically block insulin production in adult β cells and show that this leads to a relief of ER stress, AKT activation, and increased β cell proliferation.
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...
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