Ectoine Globally Hypomethylates DNA in Skin Cells and Suppresses Cancer Proliferation

Overview

Journal Mar Drugs

Publisher MDPI

Specialties Biology
Pharmacology

Date 2023 Dec 22

PMID 38132942

Authors

Majjid A Qaria

ChunYan Xu

Ran Hu

Roua A Alsubki

Mohamed Yassin Ali

Sethupathy Sivasamy

Kotb A Attia

Daochen Zhu

Affiliations

Soon will be listed here.

Abstract

Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the expression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of the well-known DNA protectant (ectoine) in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA epigenetic modifications-related gene analysis were performed. The results showed that extended ectoine treatment globally hypomethylated DNA in skin cells, especially in the CpG island (CGIs) element, and 5mC percentage was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation and did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of , , , , , , , , , , and . Overall, ectoine mildly demethylates DNA in skin cells, modulates the expression of epigenetic modification-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.

Citing Articles

Unlocking Ectoine's Postbiotic Therapeutic Promise: Mechanisms, Applications, and Future Directions.

Xingrong L, Gorish B, Qaria M, Hussain A, Abdelmula W, Zhu D Probiotics Antimicrob Proteins. 2025; .

PMID: 40072821 DOI: 10.1007/s12602-025-10506-5.

Ectoin attenuates cortisone-induced skin issues by suppression GR signaling and the UVB-induced overexpression of 11β-HSD1.

Xu D, Wu Y J Cosmet Dermatol. 2024; 23(12):4303-4314.

PMID: 39222375 PMC: 11626367. DOI: 10.1111/jocd.16516.

Integrated In Vivo and In Vitro Evaluation of a Powder-to-Hydrogel, Film-Forming Polymer Complex Base with Tissue-Protective and Microbiome-Supportive Properties.

Banov D, Song G, Foraida Z, Tkachova O, Zdoryk O, Carvalho M Gels. 2024; 10(7).

PMID: 39057470 PMC: 11276563. DOI: 10.3390/gels10070447.

References

Yeon M, Kim Y, Jung H, Jeoung D . Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma. Front Cell Dev Biol. 2020; 8:486. PMC: 7311641. DOI: 10.3389/fcell.2020.00486. View

McKinney B, Lin C, Rahman T, Oh H, Lewis D, Tseng G . DNA methylation in the human frontal cortex reveals a putative mechanism for age-by-disease interactions. Transl Psychiatry. 2019; 9(1):39. PMC: 6351569. DOI: 10.1038/s41398-019-0372-2. View

Wedeking A, Hagen-Euteneuer N, Gurgui M, Broere R, Lentzen G, Tolba R . A lipid anchor improves the protective effect of ectoine in inflammation. Curr Med Chem. 2013; 21(22):2565-72. DOI: 10.2174/0929867321666131228222730. View

Wellmerling J, Rayner R, Chang S, Kairis E, Kim S, Sharma A . Targeting the EGFR-ERK axis using the compatible solute ectoine to stabilize CFTR mutant F508del. FASEB J. 2022; 36(5):e22270. PMC: 9009300. DOI: 10.1096/fj.202100458RRR. View

Yamaga S, Murao A, Ma G, Brenner M, Aziz M, Wang P . Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice. Front Immunol. 2023; 14:1151250. PMC: 10164953. DOI: 10.3389/fimmu.2023.1151250. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Kanapathipillai M, Lentzen G, Sierks M, Park C . Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid. FEBS Lett. 2005; 579(21):4775-80. DOI: 10.1016/j.febslet.2005.07.057. View

Lyko F . The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2017; 19(2):81-92. DOI: 10.1038/nrg.2017.80. View

Xu Z, Ma A, Ma Y . RNA methylation preserves ES cell identity by chromatin silencing of retrotransposons. Signal Transduct Target Ther. 2021; 6(1):258. PMC: 8263629. DOI: 10.1038/s41392-021-00683-4. View

10.

Rueden C, Schindelin J, Hiner M, DeZonia B, Walter A, Arena E . ImageJ2: ImageJ for the next generation of scientific image data. BMC Bioinformatics. 2017; 18(1):529. PMC: 5708080. DOI: 10.1186/s12859-017-1934-z. View

11.

Coles Keeter W, Moriarty A, Akers R, Ma S, Mussbacher M, Nadler J . Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas of mice. Front Cardiovasc Med. 2023; 10:1175673. PMC: 10313069. DOI: 10.3389/fcvm.2023.1175673. View

12.

Bilstein A, Heinrich A, Rybachuk A, Mosges R . Ectoine in the Treatment of Irritations and Inflammations of the Eye Surface. Biomed Res Int. 2021; 2021:8885032. PMC: 7889333. DOI: 10.1155/2021/8885032. View

13.

Eichel A, Wittig J, Shah-Hosseini K, Mosges R . A prospective, controlled study of SNS01 (ectoine nasal spray) compared to BNO-101 (phytotherapeutic dragées) in patients with acute rhinosinusitis. Curr Med Res Opin. 2013; 29(7):739-46. DOI: 10.1185/03007995.2013.800474. View

14.

Alexander E, Mariner K, Borodyanskaya Y, Minton A, Gilmour S . Polyamine-stimulation of arsenic-transformed keratinocytes. Carcinogenesis. 2019; 40(8):1042-1051. PMC: 6735862. DOI: 10.1093/carcin/bgz115. View

15.

Strus P, Borensztejn K, Szczepankiewicz A, Lisiecki K, Czarnocki Z, Nieznanska H . Novel podophyllotoxin and benzothiazole derivative induces transitional morphological and functional changes in HaCaT cells. Toxicol In Vitro. 2021; 73:105144. DOI: 10.1016/j.tiv.2021.105144. View

16.

Kauth M, Trusova O . Topical Ectoine Application in Children and Adults to Treat Inflammatory Diseases Associated with an Impaired Skin Barrier: A Systematic Review. Dermatol Ther (Heidelb). 2022; 12(2):295-313. PMC: 8850511. DOI: 10.1007/s13555-021-00676-9. View

17.

Hseu Y, Chen X, Gowrisankar Y, Yen H, Chuang J, Yang H . The Skin-Whitening Effects of Ectoine via the Suppression of α-MSH-Stimulated Melanogenesis and the Activation of Antioxidant Nrf2 Pathways in UVA-Irradiated Keratinocytes. Antioxidants (Basel). 2020; 9(1). PMC: 7022695. DOI: 10.3390/antiox9010063. View

18.

Kang J, Lee B, Kim J, Kim M, Kim C . Identification and characterization of an ectoine biosynthesis gene cluster from Aestuariispira ectoiniformans sp. nov., isolated from seawater. Microbiol Res. 2021; 254:126898. DOI: 10.1016/j.micres.2021.126898. View

19.

Shah P, Trinh E, Qiang L, Xie L, Hu W, Prins G . Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer. Molecules. 2017; 22(2). PMC: 5361890. DOI: 10.3390/molecules22020194. View

20.

Wittmar J, Meyer S, Sieling T, Kunte J, Smiatek J, Brand I . What Does Ectoine Do to DNA? A Molecular-Scale Picture of Compatible Solute-Biopolymer Interactions. J Phys Chem B. 2020; 124(37):7999-8011. DOI: 10.1021/acs.jpcb.0c05273. View