Epigenetics (EPG) refers to all the changes in gene expression independent of primary DNA sequence modifications. The main EPG modifications include methylation of DNA cytosine bases, posttranslational modifications of histone and non-histone proteins as well as the modulation of small regulatory non-coding RNA. These changes regulate the chromatin structure and tune gene transcription and are therefore essential for normal development and differentiation of cells. Disruption of EPG processes can lead to altered gene function and malignant cellular transformations. EPG alterations have been identified as promising new targets for cancer prevention strategies as they occur early during carcinogenesis and represent potentially initiating events for cancer development.
Hypermethylation-induced transcriptional silencing of tumor suppressor genes is a frequent EPG defect in many human cancers that can be affected by decreasing the availability of methyl donors. The broad clinical application of drugs acting as DNMT inhibitors is restricted by several undesired and structural instability. Some polyphenols have been shown to directly inhibit DNMT without the associated toxicity to partially reverse hypermethylation status.
Silent chromatin is enriched in deacetylated histones, whereas active chromatin is hyperacetylated. The deregulation of histone acetylation contributes to the pathogenesis of inflammatory diseases. HDAC are often overexpressed in various types of cancer and thus, have become a major target for EPG therapy, for modulating pathways deregulations that lead to chronic disease. Polyphenols can regulate gene expression through changes in histone modifications, namely through their potent HDACs inhibitory activity.
Recently, certain anticancer agents were able to trigger the immunogenic properties of malignant cells or stimulate immune effectors, either directly or via the inhibition of the immunosuppressive checkpoints blocking antitumor immune response. Here, compounds trigger cell death that leads to exposure of immunostimulatory danger-associated molecules. This type of cell death activates and matures mostly dendritic cells, which can take up and present tumor antigens to modulate adaptive antitumor immune response. With this project we aim to innovate by assessing the immune-targeting capacity of the newly designed polyphenolic derivatives.
Novel potential chemopreventive and immunogenic anticancer agents to counteract cancer-related EPG alterations by specifically inhibiting DNMT and HDAC of cancer cells without affecting the normal cells will be prepared.
The PI?s group will develop syntheses of potential EPG modulator agents, Diederich?s group will evaluate their DNMT and HDAC inhibition activity, and binding studies will be performed by the PI's group (STD NMR) and Félix?s group using molecular docking coupled with MD simulations of the potential drugs with a crystallographic structure of corresponding human HDAC and DNMT enzymes.