Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers

Abstract

Aurora kinase A (AURKA) is frequently overexpressed in several cancers. miRNA sequencing and bioinformatics analysis indicated significant downregulation of miR-4715-3p. We found that miR-4715-3p has putative binding sites on the 3UTR region of AURKA. Upper gastrointestinal adenocarcinoma (UGC) tissue samples and cell models demonstrated significant overexpression of AURKA with downregulation of miR-4715-3p. Luciferase reporter assays confirmed binding of miR-4715-3p on the 3UTR region of AURKA. miR-4715-3p mediated a reduction in AURKA levels leading to G2/M delay, chromosomal polyploidy, and cell death. We also detected a remarkable decrease in GPX4, an inhibitor of ferroptosis, with an increase in cleaved PARP and caspase-3. Inhibition of AURKA using siRNA produced similar results, suggesting a possible link between AURKA and GPX4. Analysis of UGC samples and cell models demonstrated increased methylation levels of several CpG nucleotides upstream of miR-4715-3p. 5-Aza-2′-deoxycytidine induced demethylation of several CpG nucleotides, restoring miR-4715-3p expression, leading to downregulation of AURKA. In conclusion, our data identified a novel epigenetic mechanism mediating silencing of miR-4715-3p and induction of AURKA in UGCs. Inhibition of AURKA or reconstitution of miR-4715-3p inhibited GPX4 and induced cell death, suggesting a link between AURKA and ferroptosis.

Clinical and Biological Significances of a Ferroptosis-Related Gene Signature in Glioma

“…In upper gastrointestinal adenocarcinoma, inhibition of AURKA can reduce the expression of GPX4 and induce cell death. Furthermore (47), AURKA inhibitors may be effective in the treatment of hepatocellular carcinoma with TP53 mutation (48). Ras-GTPase-activating protein-binding protein 1 (G3BP1) is relevant in a variety of carcinogenic signaling pathways such as TP53 and RAS.…”

MicroRNA-based regulation of Aurora A kinase in breast cancer

“…Expression of AURKA among other genes was directly inhibited by miR-186 in neuroblastoma cells [79]. The epigenetic regulation of AURKA by miR-4715-3p has also been reported in gastrointestinal cancers using in silico prediction [23]. MicroRNA-490-3p suppresses hepatocellular carcinoma cell proliferation and migration by targeting AURKA [80].…”

“…AURKA has been established as a legit oncogene and thus, a vital therapeutic target in cancer [19]. Its expression has been shown to be modulated by small molecules including microRNAs in cancers [20][21][22][23].…”

Epigenetic Regulation and Nonepigenetic Mechanisms of Ferroptosis Drive Emerging Nanotherapeutics in Tumor

“…Auroral kinase A (AURKA) was significantly overexpressed in upper gastrointestinal adenocarcinoma (UGC), in which the methylation level of several CpG nucleotides upstream of miR-4715-3p increased. However, 5-aza-2′-deoxycytosine can induce upstream nucleotide demethylation of miR-4715-3p in UCG cells and restore its expression, which in turn leads to AURKA downregulation, GPX4 inhibition, and cell ferroptosis [ 63 ]. Epigenetic reprogramming of epithelial-mesenchymal transformation (EMT) regulates ferroptosis in cancer cells, as cancer cells with epithelial characteristics or dense cell populations are more susceptible to ferroptosis.…”