Hatziapostolou Maria, Koutsioumpa Marina, Zaitoun Abed M, Polytarchou Christos, Edderkaoui Mouad, Mahurkar-Joshi Swapna, Vadakekolathu Jayakumar, D'Andrea Daniel, Lay Anna Rose, Christodoulou Niki, Pham Thuy, Yau Tung-On, Vorvis Christina, Chatterji Suchit, Pandol Stephen J, Poultsides George A, Dawson David W, Lobo Dileep N, Iliopoulos Dimitrios
Department of Biosciences, John van Geest Cancer Research Centre, Centre for Systems Health and Integrated Metabolic Research, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
Vatche and Tamar Manoukian Division of Digestive Diseases, Center for Systems Biomedicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
Gastro Hep Adv. 2024 Apr 24;3(5):687-702. doi: 10.1016/j.gastha.2024.04.005. eCollection 2024.
Decoding pancreatic ductal adenocarcinoma heterogeneity and the consequent therapeutic selection remains a challenge. We aimed to characterize epigenetically regulated pathways involved in pancreatic ductal adenocarcinoma progression.
Global DNA methylation analysis in pancreatic cancer patient tissues and cell lines was performed to identify differentially methylated genes. Targeted bisulfite sequencing and in vitro methylation reporter assays were employed to investigate the direct link between site-specific methylation and transcriptional regulation. A series of in vitro loss-of-function and gain-of function studies and in vivo xenograft and the KPC ( ; ; ) mouse models were used to assess pancreatic cancer cell properties. Gene and protein expression analyses were performed in 3 different cohorts of pancreatic cancer patients and correlated to clinicopathological parameters.
We identify Hepatocyte Nuclear Factor 4A (HNF4A) as a novel target of hypermethylation in pancreatic cancer and demonstrate that site-specific proximal promoter methylation drives HNF4A transcriptional repression. Expression analyses in patients indicate the methylation-associated suppression of HNF4A expression in pancreatic cancer tissues. In vitro and in vivo studies reveal that HNF4A is a novel tumor suppressor in pancreatic cancer, regulating cancer growth and aggressiveness. As evidenced in both the KPC mouse model and human pancreatic cancer tissues, HNF4A expression declines significantly in the early stages of the disease. Most importantly, HNF4 loss correlates with poor overall patient survival.
HNF4A silencing, mediated by promoter DNA methylation, drives pancreatic cancer development and aggressiveness leading to poor patient survival.
解析胰腺导管腺癌的异质性以及随之而来的治疗选择仍然是一项挑战。我们旨在描述参与胰腺导管腺癌进展的表观遗传调控途径。
对胰腺癌患者组织和细胞系进行全基因组DNA甲基化分析，以鉴定差异甲基化基因。采用靶向亚硫酸氢盐测序和体外甲基化报告基因检测，研究位点特异性甲基化与转录调控之间的直接联系。一系列体外功能丧失和功能获得研究以及体内异种移植和KPC（；；）小鼠模型用于评估胰腺癌细胞特性。在3个不同队列的胰腺癌患者中进行基因和蛋白质表达分析，并与临床病理参数相关联。
我们确定肝细胞核因子4A（HNF4A）是胰腺癌中高甲基化的一个新靶点，并证明位点特异性近端启动子甲基化驱动HNF4A转录抑制。患者的表达分析表明胰腺癌组织中HNF4A表达存在甲基化相关的抑制。体外和体内研究表明，HNF4A是胰腺癌中的一种新型肿瘤抑制因子，可调节癌症的生长和侵袭性。正如在KPC小鼠模型和人类胰腺癌组织中所证实的，HNF4A表达在疾病早期显著下降。最重要的是，HNF4缺失与患者总体生存率低相关。
由启动子DNA甲基化介导的HNF4A沉默驱动胰腺癌的发展和侵袭性，导致患者生存率低。
