Many cancers protect themselves by deactivating Vitamin D activated genes ( Pancreatic Cancer and HNF4A in this case)
Promoter Methylation Leads to Hepatocyte Nuclear Factor 4A Loss and Pancreatic Cancer Aggressiveness
Gastro HEP Advances April 2024 DOI:https://doi.org/10.1016/j.gastha.2024.04.005
Maria Hatziapostolou. Marina Koutsioumpa ∗, Abed M. Zaitoun ∗, David W. Dawson, Dileep N. Lobo, Dimitrios Iliopoulos
Table of Contents
14X higher risk of metastatic cancer if gene had been deregulated
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.
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Study was reported on by The Guardian
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Relationship of HNF4A gene with the Vitamin D Receptor
"In summary, the HNF4A gene is associated with Vitamin D through the regulatory actions of the Vitamin D receptor, which can influence the expression and function of HNF-4α. This interaction plays a role in various metabolic processes and conditions, including liver diseases and potentially diabetes."
53+ VitaminDWiki pages have both CANCER and GENE in the title
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87+ VitaminDWiki Vitamin D Receptor pages have CANCER in the title
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