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.

• Authors: Ahmed Gomaa, Dunfa Peng, Zheng Chen, Mohammed Soutto, Khaled Abouelezz, Alejandro Corvalan, Wael El-Rifai
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 16970 (11 18 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31740746 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 3' Untranslated Regions
• Antineoplastic Agents
• MicroRNAs
• Phospholipid Hydroperoxide Glutathione Peroxidase
• AURKA protein, human
• Aurora Kinase A
• Cisplatin

Topics

• 3' Untranslated Regions
• Antineoplastic Agents (pharmacology)
• Aurora Kinase A (genetics)
• Cisplatin (pharmacology)
• DNA Methylation
• Epigenesis, Genetic
• Gastrointestinal Neoplasms (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• MicroRNAs (genetics)
• Phospholipid Hydroperoxide Glutathione Peroxidase (genetics)
• Polyploidy
• Stomach Neoplasms (drug therapy, genetics, mortality, pathology)
• Upper Gastrointestinal Tract