The influence of lactoferrin on the epigenetic characteristics of mammalian cells of different types

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Abstract

Despite the huge amount of accumulated data, the study of the main mechanisms of interaction between proteins and epigenetic mechanisms in health and various pathologies remains one of the most important problems of molecular biology. The search for various endogenous and exogenous factors affecting the epigenome of eukaryotes continues to be relevant. Lactoferrin is the second most abundant milk protein and has proven to be a very promising anti-inflammatory, antifungal, antibacterial, and anti-cancer agent. This protein can act as a transcription factor regulating the expression of some genes. However, little attention has been paid to the use of lactoferrin as an epigenetic modulating factor. This review demonstrates that lactoferrin can directly and/or indirectly influence epigenetic mechanisms (DNA methylation, histone modification, chromatin compaction, and microRNA pathways) in different types of cells, in particular cancer cells.

About the authors

Kinda Ali Sharrouf

Institute of Experimental Medicine; Saint Petersburg University

Email: kinda996@yahoo.com
ORCID iD: 0000-0003-0926-0549

Master’s student, Department of Genetics and Biotechnology, Faculty of Biology and Soil

Russian Federation, Saint Petersburg

Irina O. Suchkova

Institute of Experimental Medicine

Author for correspondence.
Email: irsuchkova@mail.ru
ORCID iD: 0000-0003-2127-0459
SPIN-code: 4155-7314
Scopus Author ID: 6602838276
ResearcherId: H-4484-2014

MD, PhD (Biology), Senior Researcher, Laboratory of Molecular Cytogenetics of Mammalian Development, Department of Molecular Genetics

Russian Federation, Saint Petersburg

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2. Fig. 1. Effect of lactoferrin complexes with oleic acid on chromatin compaction in isolated HeLa nuclei. Lf — lactoferrin; ChLfOA — human lactoferrin with oleic acid

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3. Fig. 2. Effects of estrogen receptor alpha on epigenetics mechanisms. (a) Estrogen receptor alpha has a regulatory effect on DNA methyltransferses, DNA demethylation proteins, and histone modifying enzymes, so that estrogen receptor alpha indirectly could affect chromatin status and genes expression levels. (b) Liganded estrogen receptor alpha-induced methylation mechanism. Step 1: Liganded estrogen receptor alpha binds to the estrogen responsive element in the DNA. Step 2: Estrogen receptor alpha recruits polycomb repressive complex 2, histone deacetylase 1, and enhancer of zeste homolog 2. Step 3: Histone deacetylase removes acetyl groups from the histone 3’s 27th lysine residue, and then EZH2 places three methyl groups on H3K27. Step 4: DNA methyltransferase 3B recognizes the methylated H3K27 and methylates the cytosine in a CpG island. ERα — estrogen receptor alpha; DNMT — DNA methyltransferase; HDAC — histone deacetylase 1; PRC2 — polycomb repressive complex 2; EZH2 — enhancer of zeste homolog 2; H3K27 — histone 3’s 27th lysine residue; AC — acetyl groups; 3Me — three methyl groups

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4. Fig. 3. Effect of lactoferrin on human prostate cancer cell lines DU145 and LNCaP (based on the results of Reale, Di Croce, Nuytten, Zadvornyi, Chavali, Liu and their colleagues [29–31, 21, 34, 35]). (a) Recombinant human lactoferrin causes an increase in the expression of miRNA-155 and miRNA-205 in the DU145 and LNCaP cell lines. These miRNAs were involved in the change of epigenetic status of cells. (b) miR-133a and miR-200b up-regulation after lactoferrin exposure in DU145 cell line leads to many changes in epigenetic statues. Lf — lactoferrin; ERα — estrogen receptor alpha; PR — progesterone receptor; DNMT — DNA methyltransferase; PRC2 — polycomb repressive complex 2; EZH2 — enhancer of zeste homolog 2; HDAC — histone deacetylase

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5. Fig. 4. Effect of lactoferrin on DNA methylation in Jurkat-T leukemia cells, neuroblastoma 2a cells, and breast cancer cell lines. Jurkat-T leukemia cells exposure to lactoferricin B leads to reducing the half-life, expression, and stability of DNMT1. Human lactoferrin reduces β-amyloid generation in neuroblastoma 2a cells, which in turn significantly affects DNA methylation in certain loci. Hypoxia mediated by human lactoferrin exposure in breast cancer cell lines triggers many mechanisms related to epigenetic means (depending on cell/tissue type). Hypoxia down regulates DNMT1, DNMT3A and TET enzymes, and which in the end will affect DNA methylation. Hypoxia-inducible factor 1α mediates recruitment of jumonji domain containing protein 2C to the hypoxia response elements of HIF-1 target genes that decreases trimethylation of histone H3 at lysine 9, and enhances HIF-1 binding to hypoxia response elements, thereby activating transcription of these genes. DNMT — DNA methyltransferase; TET enzymes — ten-eleven translocation enzymes (DNA demethylation enzymes); HIF-1α — hypoxia-inducible factor 1α; JMJD2C — jumonji domain containing protein 2C; HRE — hypoxia response element

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Copyright (c) 2021 Sharrouf K.A., Suchkova I.O.

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