Pancreatic Cancer protects itself deactivating HNF4A (which can be reactivated by the Vitamin D Receptor) – April 2024

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Promoter Methylation Leads to Hepatocyte Nuclear Factor 4A Loss and Pancreatic Cancer Aggressiveness

Gastro Hep Advances 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

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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Is there an association between HNF4A Gene and Vitamin D – Asked Perplexity AI July 2024 (yes)

Overview of HNF4A and Vitamin D
The HNF4A gene encodes hepatocyte nuclear factor 4 alpha (HNF4α), a nuclear receptor and transcription factor that plays a crucial role in the regulation of gene expression in the liver, pancreas, and other tissues. It is involved in various metabolic processes, including glucose and lipid metabolism, and is also implicated in certain forms of diabetes, such as Maturity Onset Diabetes of the Young 1 (MODY1).Vitamin D, on the other hand, exerts its effects primarily through the vitamin D receptor (VDR), another nuclear receptor that regulates the expression of numerous genes involved in calcium homeostasis, immune function, and other physiological processes.

Interactions Between HNF4A and Vitamin D
Recent research has elucidated a direct interaction between the vitamin D receptor (VDR) and HNF4α. Specifically, VDR has been shown to target HNF4α, influencing its activity and thereby affecting metabolic processes:

• Mechanistic Interactions: Studies have demonstrated that VDR can physically interact with HNF4α. This interaction suggests that VDR can modulate the activity of HNF4α, potentially affecting the expression of genes regulated by HNF4α. For instance, overexpression of HNF4α has been shown to improve conditions such as high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD), indicating a protective role mediated through VDR-HNF4α interactions.
• Gene Regulation: HNF4α is known to regulate a variety of genes involved in drug metabolism, including several cytochrome P450 (CYP) enzymes. The modulation of HNF4α by VDR suggests that vitamin D status could influence the expression of these metabolic genes, thereby impacting drug metabolism and other metabolic pathways.

Implications for Health and Disease
The interaction between VDR and HNF4α has significant implications for health and disease management:

• Metabolic Disorders: Given HNF4α's role in glucose and lipid metabolism, its interaction with VDR suggests that vitamin D status could influence metabolic health. This is particularly relevant in conditions like diabetes and NAFLD, where metabolic regulation is crucial.
• Autoimmune Diseases: The regulation of immune-related genes by VDR and its interaction with HNF4α may also play a role in autoimmune diseases. Vitamin D deficiency has been associated with increased risk of autoimmune conditions, and the modulation of immune gene expression through VDR-HNF4α interactions could be a contributing factor.

Conclusion
In summary, there is a significant association between the HNF4A gene and vitamin D, primarily mediated through the interaction of VDR with HNF4α. This interaction influences the regulation of various genes involved in metabolic and immune processes, highlighting the potential impact of vitamin D on conditions such as diabetes, NAFLD, and autoimmune diseases.
References:

1. NCBI
2. Nature
3. JBC
4. ResearchGate

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VitaminDWiki – Cancer - Pancreatic category contains:

59 items in Cancer-Pancreatic

Risk of Pancreatic Cancer significantly reduced by each of:
Vitamin D, Vitamin K, Magnesium, Vitamin D Receptor Activators, and Omega-3
Perhaps the combination would reduce PC risk by >90%
   if taken for at least 2, and perhaps 5 years

• Pancreatic cancer 55 percent less likely if optimal vitamin D (vs low) – Nov 2017
• Pancreatic Cancer survival 2.3 X more likely if good level of Vitamin D – meta-analysis Sept 2023
• Pancreatic Cancer is increasing – Vitamin D and Omega-3 should reduce the risk
• Pancreatic Cancer – live a year longer if have high vitamin D and good Vitamin D Receptor – Aug 2018
• People consuming more Vitamin K1 were 40 percent less likely to get Pancreatic Cancer – Oct 2021
• Pancreatic Cancer risk increased 24 percent for every 100 mg less of Magnesium intake – Dec 2015

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VitaminDWiki - 4 studies in both categories Pancreatic Cancer and Vitamin D Receptor

This list is automatically updated

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Vitamin D Receptor (Cancers OR Viruses) - many studies 95 as of July 2024

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VitaminDWiki - Vitamin D Receptor activation can be increased in 13+ ways

Resveratrol,  Omega-3,   Magnesium,  Zinc,   Quercetin,   non-daily Vit D,   Curcumin,   Berberine,  intense exercise, Butyrate   Sulforaphane  Metflormin (Kidney)   Ginger,   Essential oils, etc  Note: The founder of VitaminDWiki uses 10 of the many VDR activators