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

Ahmed Gomaa, Dunfa Peng, Zheng Chen, Mohammed Soutto, Khaled Abouelezz, Alejandro Corvalan, Wael El-Rifai

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number16970
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Aurora Kinase A
Gastrointestinal Neoplasms
Epigenomics
Down-Regulation
decitabine
Adenocarcinoma
Cell Death
Nucleotides
Polyploidy
Computational Biology
Luciferases
MicroRNAs
Caspase 3
Methylation
Small Interfering RNA

ASJC Scopus subject areas

  • General

Cite this

Gomaa, A., Peng, D., Chen, Z., Soutto, M., Abouelezz, K., Corvalan, A., & El-Rifai, W. (2019). Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers. Scientific reports, 9(1), [16970]. https://doi.org/10.1038/s41598-019-53174-6

Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers. / Gomaa, Ahmed; Peng, Dunfa; Chen, Zheng; Soutto, Mohammed; Abouelezz, Khaled; Corvalan, Alejandro; El-Rifai, Wael.

In: Scientific reports, Vol. 9, No. 1, 16970, 01.12.2019.

Research output: Contribution to journalArticle

Gomaa, A, Peng, D, Chen, Z, Soutto, M, Abouelezz, K, Corvalan, A & El-Rifai, W 2019, 'Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers', Scientific reports, vol. 9, no. 1, 16970. https://doi.org/10.1038/s41598-019-53174-6
Gomaa, Ahmed ; Peng, Dunfa ; Chen, Zheng ; Soutto, Mohammed ; Abouelezz, Khaled ; Corvalan, Alejandro ; El-Rifai, Wael. / Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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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.",
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