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Pharmacoepigenomics circuits induced by a novel retinoid-polyamine conjugate in human immortalized keratinocytes

The Pharmacogenomics Journal volume 21, pages 638–648 (2021)Cite this article

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Abstract

Retinoids are widely used in diseases spanning from dermatological lesions to cancer, but exhibit severe adverse effects. A novel all-trans-Retinoic Acid (atRA)-spermine conjugate (termed RASP) has shown previously optimal in vitro and in vivo anti-inflammatory and anticancer efficacy, with undetectable teratogenic and toxic side-effects. To get insights, we treated HaCaT cells which resemble human epidermis with IC50 concentration of RASP and analyzed their miRNA expression profile. Gene ontology analysis of their predicted targets indicated dynamic networks involved in cell proliferation, signal transduction and apoptosis. Furthermore, DNA microarrays analysis verified that RASP affects the expression of the same categories of genes. A protein–protein interaction map produced using the most significant common genes, revealed hub genes of nodal functions. We conclude that RASP is a synthetic retinoid derivative with improved properties, which possess the beneficial effects of retinoids without exhibiting side-effects and with potential beneficial effects against skin diseases including skin cancer.

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Fig. 1: Expression profile of miRNAs after RASP treatment of HaCat cells.
Fig. 2: Expression profiling of miRNAs that have also been associated with skin cancer and GO analysis of their predicted targets.
Fig. 3: Expression profile of genes after RASP treated HaCat cells.
Fig. 4: Venn diagram of genes that are affected after treatment of keratinocytes with RASP.
Fig. 5: Clusters and their respective molecular function over the physical protein–protein interactions network with the protein products of the 546 statistically significant differentially expressed genes.
Fig. 6: Verification of expression level alterations of genes implicated in apoptosis, signaling and translation regulation via RT-qPCR.

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Acknowledgements

I. Skeparnias is supported by a fellowship from the “RIBOMAP” Grant implemented under the Operational Program: Human Resources Development, Education and Lifelong Learning which is co-funded by the European Social Fund (ESF) and National Resources (MIS 5047175 to C.S.). G. Kyriakopoulos is supported by a PhD fellowship from the INSPIRED (MIS 5002550), which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund).

Funding

The work was supported by INSPIRED (MIS 5002550), which is implemented under the Action “Reinforcement of the Research and Innovation Infrastructure”, funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund).

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  1. Dimitrios Anastasakis

    Present address: National Institute of Musculoskeletal and Arthritis and Skin, Bethesda, MD, USA

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, University of Patras, Patras, Greece

    Katerina Grafanaki, Ilias Skeparnias, Dimitrios Anastasakis, George Kyriakopoulos, Constantinos Stathopoulos & Denis Drainas

  2. Department of Dermatology, University Hospital of Patras, School of Medicine, University of Patras, Patras, Greece

    Katerina Grafanaki

  3. Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

    Christos K. Kontos & Andreas Scorilas

  4. Department of Medical Physics, School of Medicine, University of Patras, Patras, Greece

    Aigli Korfiati

  5. InSyBio Ltd,19 Staple Gardens SO23 8SR, Winchester, Hampshire, UK

    Konstantinos Theofilatos & Seferina Mavroudi

  6. Department of Chemistry, University of Patras, Patras, Greece

    George Magoulas & Dionissios Papaioannou

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Grafanaki, K., Skeparnias, I., Kontos, C.K. et al. Pharmacoepigenomics circuits induced by a novel retinoid-polyamine conjugate in human immortalized keratinocytes. Pharmacogenomics J 21, 638–648 (2021). https://doi.org/10.1038/s41397-021-00241-9

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