Background: Zinc-oxide (ZnO) nanoparticles (NPs) have wide industrial and biomedical applications. Determining the mechanisms of NPs action is challenging in clinical application particularly in future cancer therapy. However, the genetic and epigenetics effect of ZnO-NPs on autophagy (ATG) and apoptosis related long non-coding RNA (lncRNA) have not been studied.
Methods: ZnO-NPs were synthesized, characterized, and evaluated their effects on MCF-7 cells. In the following, breast cancer cells were treated with ZnO-NPs in the presence or absence of N-acetyl-L-cysteine (NAC, reactive oxygen species [ROS] inhibitor), 3-methyladenine (3-MA, ATG inhibitor), and Z-VAD-FMK (apoptosis inhibitor). Finally, genetic and epigenetic modification on ATG and apoptosis related lncRNA, such as DNA methylation, histones modification, and alteration in lncRNA expression were investigated.
Results: Comparison between non-exposed and exposed cells revealed a significant increase in GAS5 expression, whereas XIST, TUG1, and MALAT1 were significantly downregulated. Histone modification analysis demonstrated enrichment of H3K4me3 at the GAS5 promoter. In contrast, H3K27me3 levels were significantly increased at the promoters of XIST, TUG1, and MALAT1. Consistently, promoter methylation analysis showed decreased methylation in GAS5, while methylation levels were significantly increased in XIST, TUG1, and MALAT1.
Conclusion: It seems that lncRNA modulate the crosstalk between ATG and apoptosis via regulating the expression of related genes. The present study may provide new insights into the mechanism of NPs interference with ATG and apoptosis related lncRNA in cancer therapeutic.