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

Gomaa A.; Peng D.; Chen Z.; Soutto M.; Abouelezz K.; Corvalan A.; El-Rifai W.

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.

Más información

Título según WOS: Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers
Título según SCOPUS: Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers
Título de la Revista: SCIENTIFIC REPORTS
Volumen: 9
Editorial: NATURE PORTFOLIO
Fecha de publicación: 2019
Idioma: English
DOI:

10.1038/s41598-019-53174-6

Notas: ISI, SCOPUS