Maria Hatziapostolou
Promoter methylation leads to Hepatocyte Nuclear Factor 4A loss and pancreatic cancer aggressiveness
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
Authors
Marina Koutsioumpa
Abed M. Zaitoun
Christos Polytarchou
Mouad Edderkaoui
Swapna Mahurkar-Joshi
Jayakumar Vadakekolathu
Daniel D'Andrea
Anna Rose Lay
Niki Christodoulou
Thuy Pham
Tung-On Yau
Christina Vorvis
Suchit Chatterji
Stephen J. Pandol
George A. Poultsides
David W. Dawson
DILEEP LOBO dileep.lobo@nottingham.ac.uk
Professor of Gastrointestinal Surgery
Dimitrios Iliopoulos
Abstract
Background and Aims: 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. Methods: 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 (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre) 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. Results: 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. Conclusion: HNF4A silencing, mediated by promoter DNA methylation, drives pancreatic cancer development and aggressiveness leading to poor patient survival.
Citation
Hatziapostolou, M., Koutsioumpa, M., Zaitoun, A. M., Polytarchou, C., Edderkaoui, M., Mahurkar-Joshi, S., …Iliopoulos, D. (2024). Promoter methylation leads to Hepatocyte Nuclear Factor 4A loss and pancreatic cancer aggressiveness. Gastro Hep Advances, 3(5), 687-702. https://doi.org/10.1016/j.gastha.2024.04.005
Journal Article Type | Article |
---|---|
Acceptance Date | Apr 2, 2024 |
Online Publication Date | Apr 23, 2024 |
Publication Date | Apr 23, 2024 |
Deposit Date | Apr 4, 2024 |
Publicly Available Date | Apr 4, 2024 |
Journal | Gastro Hep Advances |
Print ISSN | 2772-5723 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 3 |
Issue | 5 |
Pages | 687-702 |
DOI | https://doi.org/10.1016/j.gastha.2024.04.005 |
Keywords | Pancreatic Cancer, DNA methylation, Epigenetics, HNF4A |
Public URL | https://nottingham-repository.worktribe.com/output/33290816 |
Publisher URL | https://www.sciencedirect.com/science/article/pii/S2772572324000554 |
Files
AAM Gastro Hep Adv
(4.5 Mb)
PDF
Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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