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.

中文翻译：

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HNF1A 招募 KDM6A 来激活抑制胰腺癌的分化腺泡细胞程序。


胰腺外分泌分化的转录调节因子的缺陷与胰腺肿瘤的发生有关，但其分子机制尚不清楚。编码转录因子 HNF1A 的基因座含有胰腺导管腺癌 (PDAC) 的易感性变异，而编码赖氨酸特异性去甲基化酶 6A 的 KDM6A 则携带 PDAC 的体细胞突变。在这里，我们发现胰腺特异性 Hnf1a 无效突变转录组与 Kdm6a 突变的转录组表型相似，并且这两种缺陷与 KrasG12D 协同作用，导致具有肉瘤样特征的 PDAC。我们结合遗传、表观基因组和生化研究表明，HNF1A 将 KDM6A 招募到胰腺腺泡细胞的基因组结合位点。这重塑了腺泡增强子景观，激活分化的腺泡细胞程序，并间接抑制致癌基因和上皮间质转化基因。我们还鉴定了表现出 HNF1A/KDM6A 缺陷分子表型的非经典 PDAC 样本的子集。这些发现提供了 HNF1A 缺陷促进 PDAC 的直接遗传证据。他们还将 KDM6A 缺陷的肿瘤抑制作用与 PDAC 亚型定义背后的细胞特异性分子机制联系起来。