Sulforaphane Protects Against Ethanol-Induced Apoptosis in Human Neural Crest Cells Through Diminishing Ethanol-Induced Hypermethylation at the Promoters of the Genes Encoding the Inhibitor of Apoptosis Proteins

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Feb 26

PMID 33634123

Citations 4

Authors

Yihong Li

Huadong Fan

Fuqiang Yuan

Lanhai Lu

Jie Liu

Wenke Feng

Huang-Ge Zhang

Shao-Yu Chen

Affiliations

Soon will be listed here.

Abstract

The neural crest cell (NCC) is a multipotent progenitor cell population that is sensitive to ethanol and is implicated in the Fetal Alcohol Spectrum Disorders (FASD). Studies have shown that sulforaphane (SFN) can prevent ethanol-induced apoptosis in NCCs. This study aims to investigate whether ethanol exposure can induce apoptosis in human NCCs (hNCCs) through epigenetically suppressing the expression of anti-apoptotic genes and whether SFN can restore the expression of anti-apoptotic genes and prevent apoptosis in ethanol-exposed hNCCs. We found that ethanol exposure resulted in a significant increase in the expression of DNMT3a and the activity of DNMTs. SFN treatment diminished the ethanol-induced upregulation of DNMT3a and dramatically reduced the activity of DNMTs in ethanol-exposed hNCCs. We also found that ethanol exposure induced hypermethylation at the promoter regions of two inhibitor of apoptosis proteins (IAP), NAIP and XIAP, in hNCCs, which were prevented by co-treatment with SFN. SFN treatment also significantly diminished ethanol-induced downregulation of NAIP and XIAP in hNCCs. The knockdown of DNMT3a significantly enhanced the effects of SFN on preventing the ethanol-induced repression of NAIP and XIAP and apoptosis in hNCCs. These results demonstrate that SFN can prevent ethanol-induced apoptosis in hNCCs by preventing ethanol-induced hypermethylation at the promoter regions of the genes encoding the IAP proteins and diminishing ethanol-induced repression of NAIP and XIAP through modulating DNMT3a expression and DNMT activity.

Citing Articles

Sulforaphane Wrapped in Self-Assembled Nanomicelle Enhances the Effect of Sonodynamic Therapy on Glioma.

Li Y, Yang X, Wei Z, Niu H, Wu L, Chen C Pharmaceutics. 2025; 17(1).

PMID: 39861683 PMC: 11769538. DOI: 10.3390/pharmaceutics17010034.

Neural crest cells and fetal alcohol spectrum disorders: Mechanisms and potential targets for prevention.

Chen S, Kannan M Pharmacol Res. 2023; 194:106855.

PMID: 37460002 PMC: 10528842. DOI: 10.1016/j.phrs.2023.106855.

Fetal alcohol spectrum disorders.

Popova S, Charness M, Burd L, Crawford A, Hoyme H, Mukherjee R Nat Rev Dis Primers. 2023; 9(1):11.

PMID: 36823161 DOI: 10.1038/s41572-023-00420-x.

Ethanol exposure disrupted the formation of radial glial processes and impaired the generation and migration of outer radial glial cells in forebrain organoids derived from human embryonic stem cells.

Lu L, Yuan F, Fan H, Li Y, Liu J, Feng W Exp Neurol. 2023; 362:114325.

PMID: 36669750 PMC: 9992138. DOI: 10.1016/j.expneurol.2023.114325.

Up-regulation of microRNA-34a mediates ethanol-induced impairment of neural crest cell migration in vitro and in zebrafish embryos through modulating epithelial-mesenchymal transition by targeting Snail1.

Fan H, Li Y, Yuan F, Lu L, Liu J, Feng W Toxicol Lett. 2022; 358:17-26.

PMID: 35038560 PMC: 9058190. DOI: 10.1016/j.toxlet.2022.01.004.

References

Meeran S, Patel S, Li Y, Shukla S, Tollefsbol T . Bioactive dietary supplements reactivate ER expression in ER-negative breast cancer cells by active chromatin modifications. PLoS One. 2012; 7(5):e37748. PMC: 3360625. DOI: 10.1371/journal.pone.0037748. View

Goffredo D, Rigamonti D, Zuccato C, Tartari M, Valenza M, Cattaneo E . Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease. Pharmacol Res. 2005; 52(2):140-50. DOI: 10.1016/j.phrs.2005.01.006. View

Sokol R, Delaney-Black V, Nordstrom B . Fetal alcohol spectrum disorder. JAMA. 2003; 290(22):2996-9. DOI: 10.1001/jama.290.22.2996. View

Yuan F, Chen X, Liu J, Feng W, Cai L, Wu X . Sulforaphane restores acetyl-histone H3 binding to Bcl-2 promoter and prevents apoptosis in ethanol-exposed neural crest cells and mouse embryos. Exp Neurol. 2017; 300:60-66. PMC: 5745274. DOI: 10.1016/j.expneurol.2017.10.020. View

Harada K, Toyooka S, Shivapurkar N, Maitra A, Reddy J, Matta H . Deregulation of caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res. 2002; 62(20):5897-901. View

Chen X, Liu J, Feng W, Wu X, Chen S . MiR-125b protects against ethanol-induced apoptosis in neural crest cells and mouse embryos by targeting Bak 1 and PUMA. Exp Neurol. 2015; 271:104-11. PMC: 4586365. DOI: 10.1016/j.expneurol.2015.04.026. View

Weiss K, Runz H, Noe B, Gotthardt D, Merle U, Ferenci P . Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010; 33 Suppl 3:S233-40. DOI: 10.1007/s10545-010-9123-5. View

Zhou F, Balaraman Y, Teng M, Liu Y, Singh R, Nephew K . Alcohol alters DNA methylation patterns and inhibits neural stem cell differentiation. Alcohol Clin Exp Res. 2011; 35(4):735-46. PMC: 3076804. DOI: 10.1111/j.1530-0277.2010.01391.x. View

Basavarajappa B, Subbanna S . Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits. Brain Sci. 2016; 6(2). PMC: 4931489. DOI: 10.3390/brainsci6020012. View

10.

Haycock P, Ramsay M . Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol Reprod. 2009; 81(4):618-27. DOI: 10.1095/biolreprod.108.074682. View

11.

Pena C, Monk C, Champagne F . Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLoS One. 2012; 7(6):e39791. PMC: 3383683. DOI: 10.1371/journal.pone.0039791. View

12.

Li J, Su X, Dai L, Chen N, Fang C, Dong Z . Temporal DNA methylation pattern and targeted therapy in colitis-associated cancer. Carcinogenesis. 2019; 41(2):235-244. DOI: 10.1093/carcin/bgz199. View

13.

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

14.

Kang K, Piao M, Hyun Y, Zhen A, Cho S, Ahn M . Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells. Exp Mol Med. 2019; 51(4):1-14. PMC: 6465248. DOI: 10.1038/s12276-019-0238-y. View

15.

Holcik M, Thompson C, Yaraghi Z, Lefebvre C, Mackenzie A, Korneluk R . The hippocampal neurons of neuronal apoptosis inhibitory protein 1 (NAIP1)-deleted mice display increased vulnerability to kainic acid-induced injury. Proc Natl Acad Sci U S A. 2000; 97(5):2286-90. PMC: 15793. DOI: 10.1073/pnas.040469797. View

16.

Jones P, Liang G . Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009; 10(11):805-11. PMC: 2848124. DOI: 10.1038/nrg2651. View

17.

Teodoridis J, Strathdee G, Brown R . Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker. Drug Resist Updat. 2004; 7(4-5):267-78. DOI: 10.1016/j.drup.2004.06.005. View

18.

Cartwright M, Smith S . Increased cell death and reduced neural crest cell numbers in ethanol-exposed embryos: partial basis for the fetal alcohol syndrome phenotype. Alcohol Clin Exp Res. 1995; 19(2):378-86. DOI: 10.1111/j.1530-0277.1995.tb01519.x. View

19.

Dunty Jr W, Chen S, Zucker R, Dehart D, Sulik K . Selective vulnerability of embryonic cell populations to ethanol-induced apoptosis: implications for alcohol-related birth defects and neurodevelopmental disorder. Alcohol Clin Exp Res. 2001; 25(10):1523-35. View

20.

Sakharkar A, Tang L, Zhang H, Chen Y, Grayson D, Pandey S . Effects of acute ethanol exposure on anxiety measures and epigenetic modifiers in the extended amygdala of adolescent rats. Int J Neuropsychopharmacol. 2014; 17(12):2057-67. PMC: 4213292. DOI: 10.1017/S1461145714001047. View