AURKA induces EMT by regulating histone modification through Wnt/β-catenin and PI3K/Akt signaling pathway in gastric cancer

Abstract

Gastric cancer, a highly invasive and aggressive malignancy, is the third leading cause of death from cancer worldwide. Genetic association studies have successfully revealed several important genes consistently associated with gastric cancer to date. However, these robust gastric cancer-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. In the present study, we performed an alternative approach, a gene expression-based genome-wide association study (eGWAS) across 13 independent microarray experiments (including 251 gastric cancer cases and 428 controls), to identify top candidates (p<0.00001). Additionally, we conducted gene ontology analysis, pathway analysis and network analysis and identified aurora kinase A (AURKA) as our candidate. We observed that MLN8237, which is a specific inhibitor of AURKA, decreased the β-catenin and the phosphorylation of Akt1 and GSK-3β, as well as blocked the Akt and Wnt signaling pathways. Furthermore, MLN8237 arrested the cells in the G2/M phase. The activity of Wnt and Akt signaling pathways affected the level of histone methylation significantly, and we supposed that MLN8237 affected the level of histone methylation through these two signaling pathways. Additionally, the treatment of MLN8237 influenced the level of H3K4 me1/2/3 and H3K27 me1/2/3. Chip data on cell lines suggested that MLN8237 increases the level of H3K27 me3 on the promoter of Twist and inhibits EMT (epithelial-mesenchymal transition). In summary, AURKA is a potential therapeutic target in gastric cancer and induces EMT through histone methylation.

UBE2C induces EMT through Wnt/β-catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A

“…The results indicated that AURKA was a hub gene based on linkage analysis (25). Considering previous studies, we hypothesized that there may exist some genes that are co-activated with AURKA in gastric cancer.…”

“…In the previous study, we analyzed the 184 differentially expressed genes in gastric cancer from the eGWAS and revealed AURKA is at the core of the gastric cancer linkage network (25). AURKA is a serine/threonine kinase that localizes to spindle poles, and ensures the correct assembly of cellular components during mitosis in normal cells (26).…”

Ginsenoside Rg1 Ameliorates Cigarette Smoke-Induced Airway Fibrosis by Suppressing the TGF-β1/Smad Pathway In Vivo and In Vitro

“…It should be noted that apart from the Smad pathway, TGF- β -related protein also activates other signaling pathways, such as MEK/ERK, Wnt/ β -catenin, and PI3K/Akt [35, 36]. Further investigations into the relationships between ginsenoside Rg1 and Smad-independent pathways are warranted.…”

The Lnc RNA SPRY4-IT1 Modulates Trophoblast Cell Invasion and Migration by Affecting the Epithelial-Mesenchymal Transition

“…β-catenin is the key transcriptional activator in the canonical Wnt signalling pathway in the nucleus, and HuR represses Wnt/β-catenin-mediated transcriptional activity by promoting the cytoplasmic localization of β-catenin48. Therefore, EMT appears to be regulated by the Wnt/β-catenin pathway4950. These results, combined with the change in WNT3 and WNT5B expression with alterations in SPRY4-IT1 expression in HTR-8/SVneo cells, indicate that SPRY4-IT1 might regulate the EMT in trophoblast cells through Wnt/β-catenin signalling.…”