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Article

Differential and Overlapping Effects of Melatonin and Its Metabolites on Keratinocyte Function: Bioinformatics and Metabolic Analyses

1
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2
Department of Oncology, Nicolaus Copernicus University Medical College, Romanowskiej Str. 2, 85-796 Bydgoszcz, Poland
3
Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany
4
Department of Genetics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
5
Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Team 12, Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d’Azur, INSERM U1065, 06200 Nice, France
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Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229, USA
8
Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL 35294, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Equal senior-author contribution.
Academic Editor: Helen Galley
Antioxidants 2021, 10(4), 618; https://doi.org/10.3390/antiox10040618
Received: 18 February 2021 / Revised: 13 April 2021 / Accepted: 14 April 2021 / Published: 17 April 2021
(This article belongs to the Special Issue Melatonin and Vitamin D in Diseases and Health)
We investigated the effects of melatonin and its selected metabolites, i.e., N1-Acetyl-N2-formyl-5-methoxykynurenamine (AFMK) and 6-hydroxymelatonin (6(OH)Mel), on cultured human epidermal keratinocytes (HEKs) to assess their homeostatic activities with potential therapeutic implications. RNAseq analysis revealed a significant number of genes with distinct and overlapping patterns, resulting in common regulation of top diseases and disorders. Gene Set Enrichment Analysis (GSEA), Reactome FIViZ, and Ingenuity Pathway Analysis (IPA) showed overrepresentation of the p53-dependent G1 DNA damage response gene set, activation of p53 signaling, and NRF2-mediated antioxidative pathways. Additionally, GSEA exhibited an overrepresentation of circadian clock and antiaging signaling gene sets by melatonin derivatives and upregulation of extension of telomere signaling in HEKs, which was subsequently confirmed by increased telomerase activity in keratinocytes, indicating possible antiaging properties of metabolites of melatonin. Furthermore, Gene Ontology (GO) showed the activation of a keratinocyte differentiation program by melatonin, and GSEA indicated antitumor and antilipidemic potential of melatonin and its metabolites. IPA also indicated the role of Protein Kinase R (PKR) in interferon induction and antiviral response. In addition, the test compounds decreased lactate dehydrogenase A (LDHA) and lactate dehydrogenase C (LDHC) gene expression. These results were validated by qPCR and by Seahorse metabolic assay with significantly decreased glycolysis and lactate production under influence of AFMK or 6(OH)Mel in cells with a low oxygen consumption rate. In summary, melatonin and its metabolites affect keratinocytes’ functions via signaling pathways that overlap for each tested molecule with some distinctions. View Full-Text
Keywords: melatonin; metabolites of melatonin; RNA-sequencing; human keratinocytes; mitochondrial metabolism melatonin; metabolites of melatonin; RNA-sequencing; human keratinocytes; mitochondrial metabolism
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MDPI and ACS Style

Stefan, J.; Kim, T.-K.; Schedel, F.; Janjetovic, Z.; Crossman, D.K.; Steinbrink, K.; Slominski, R.M.; Zmijewski, J.; Tulic, M.K.; Reiter, R.J.; Kleszczyński, K.; Slominski, A.T. Differential and Overlapping Effects of Melatonin and Its Metabolites on Keratinocyte Function: Bioinformatics and Metabolic Analyses. Antioxidants 2021, 10, 618. https://doi.org/10.3390/antiox10040618

AMA Style

Stefan J, Kim T-K, Schedel F, Janjetovic Z, Crossman DK, Steinbrink K, Slominski RM, Zmijewski J, Tulic MK, Reiter RJ, Kleszczyński K, Slominski AT. Differential and Overlapping Effects of Melatonin and Its Metabolites on Keratinocyte Function: Bioinformatics and Metabolic Analyses. Antioxidants. 2021; 10(4):618. https://doi.org/10.3390/antiox10040618

Chicago/Turabian Style

Stefan, Joanna, Tae-Kang Kim, Fiona Schedel, Zorica Janjetovic, David K. Crossman, Kerstin Steinbrink, Radomir M. Slominski, Jaroslaw Zmijewski, Meri K. Tulic, Russel J. Reiter, Konrad Kleszczyński, and Andrzej T. Slominski. 2021. "Differential and Overlapping Effects of Melatonin and Its Metabolites on Keratinocyte Function: Bioinformatics and Metabolic Analyses" Antioxidants 10, no. 4: 618. https://doi.org/10.3390/antiox10040618

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