Background: Class I selective histone deacetylase inhibitors (HDACi) have been previously demonstrated to not only increase major histocompatibility complex class I surface expression in Merkel cell carcinoma (MCC) cells by restoring the antigen processing and presentation machinery, but also exert anti-tumoral effect by inducing apoptosis. Both phenomena could be due to induction of type I interferons (IFN), as has been described for HDACi. However, the mechanism of IFN induction under HDACi is not fully understood because the expression of IFNs is regulated by both activating and inhibitory signaling pathways. Our own preliminary observations suggest that this may be caused by suppression of HES1.
Methods: The effect of the class I selective HDACi domatinostat and IFNα on cell viability and the apoptosis of MCPyV-positive (WaGa, MKL-1) and -negative (UM-MCC 34) MCC cell lines, as well as, primary fibroblasts were assessed by colorimetric methods or measuring mitochondrial membrane potential and intracellular caspase-3/7, respectively. Next, the impact of domatinostat on IFNA and HES1 mRNA expression was measured by RT-qPCR; intracellular IFNα production was detected by flow cytometry. To confirm that the expression of IFNα induced by HDACi was due to the suppression of HES1, it was silenced by RNA interference and then mRNA expression of IFNA and IFN-stimulated genes was assessed.
Results: Our studies show that the previously reported reduction in viability of MCC cell lines after inhibition of HDAC by domatinostat is accompanied by an increase in IFNα expression, both of mRNA and at the protein level. We confirmed that treatment of MCC cells with external IFNα inhibited their proliferation and induced apoptosis. Re-analysis of existing single-cell RNA sequencing data indicated that induction of IFNα by domatinostat occurs through repression of HES1, a transcriptional inhibitor of IFNA; this was confirmed by RT-qPCR. Finally, siRNA-mediated silencing of HES1 in the MCC cell line WaGa not only increased mRNA expression of IFNA and IFN-stimulated genes but also decreased cell viability.
Conclusion: Our results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis.
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http://dx.doi.org/10.1007/s00432-023-04733-y | DOI Listing |
Biol Pharm Bull
December 2024
Laboratory of Clinical and Translational Physiology, Kyoto Pharmaceutical University.
Mucociliary clearance (MCC) is a host defense mechanism of the respiratory system. Beating cilia plays a crucial role in the MCC process and ciliary beat frequency (CBF) is activated by several factors including elevations of the intracellular cAMP concentration ([cAMP]), intracellular Ca concentration ([Ca]), and intracellular pH (pH). In this study, we investigated whether an artichoke-extracted component cynaropicrin could be a beneficial compound for improving MCC.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China. Electronic address:
Current chemotherapeutic efficacy is limited by the rapid development of multidrug resistance (MDR) in hepatocellular carcinoma (HCC). In this study, 66 MDR-related hub genes in drug-resistant HCC were identified through combined analysis of differential expressed genes (DEGs), gene functional enrichment, Cox proportional regression, weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network construction. A prognostic risk model was established through the LASSO-Cox regression analysis.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China; Peptide and small molecule drug R&D plateform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, Hunan, China. Electronic address:
Anticancer peptides (ACPs) demonstrate significant potential in clinical cancer treatment due to their ability to selectively target and kill cancer cells. In recent years, numerous artificial intelligence (AI) algorithms have been developed. However, many predictive methods lack sufficient wet lab validation, thereby constraining the progress of models and impeding the discovery of novel ACPs.
View Article and Find Full Text PDFASAIO J
December 2024
Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler.
View Article and Find Full Text PDFIran J Pathol
April 2024
Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Background & Objective: Mast cells play a role in the immune responses to fatty liver disease. The present study aimed to investigate the diagnostic value of hepatic mast cell concentration (MCC) in NAFLD and NASH severity and fibrosis grade.
Methods: The present cross-sectional unremarkable hepatic histology, NAFLD, or NASH cases were enrolled.
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