Gastric Cancer Candidate Gene AURKA Induces EMT By Regulating Histone Modification

Gastric cancer, a highly invasive and aggressive malignancy, is the second leading cause of death from cancer worldwide. As traditional chemotherapy and radiotherapy treatment have extremely limitions for advanced gastric cancer, therefore, investigations into its initiation and development are of great importance. The treatment of gastric cancer based on the molecular characteristics is the new direction of gastric cancer targeted therapy at present.To overview which molecular functions were most shared in the highest ranked genes in our gastric cancer eGWAS, we took 184 genes from our eGWAS. Next, we estimated the enrichment of GO terms, KEGG pathway analysis, network analysis and the results demonstrated that AURKA is the center of the network.Western blotting results demonstrated the reduced expression of β-catenin, p-AKT1 and p-GSK-3β. These results confirmed that MLN8237 suppressed the activity of the Wnt/β-catenin and PI3K/Akt signaling pathways. And treatment with MLN8237 significantly suppressed the invasion of cells. MLN8237 treatment suppresses gastric cancer tumorigenesis in vitro.After the treatment of FH535, the levels of H3K4 me1/me2 and H3K27 me3 were increased, H3K4 me3 and H3K27me1/2 were decreased in gastric cancer, colon cancer and hepatocarcinoma cells. The levels of H3K4me1/2/3 and H3K27 me2/3 were increased, and those of H3K27 me1 were decreased following treatment with LY294002 in gastric cancer, colon cancer and hepatocarcinoma cells. Wnt3 a and EGF produced the opposite effect.The results demonstrated an increased expression of H3K27 me2/3 in the gastric cancer cell lines. However, the expression of H3K4 me1/2/3 and H3K27 me1 showed no consistent tendency following MLN8237 treatment in these gastric cancer cell lines. To examine the functional role of H3K27me3 in the promoter region of Twist, we performed ChIP-qPCR. The results showed that the level of H3K27 me3 in the promoter of Twist increased following MLN8237 treatment. Treatment with MLN8237 suppressed the growth of gastric cancer cells compared with the DMSO-treated group significantly. Additionally, to confirm the role of AURKA, we established a subcutaneous gastric carcinoma model using the MGC-803 cells. Compared with the Lenti-NC-treated MGC-803 cells, the Lenti-siAURKA-treated tumor was suppressed significantly. In addition, immunohistochemistry was used to compare the H3K27me3 and Ki67 expression levels in these groups. For cell proliferation markers, Lenti-siAURKA treatment decreased the expression of Ki67. MLN8237 and Lenti-siAURKA treatment increased the expression of H3K27me3 in gastric carcinoma models.In conclusion, AURKA was markedly differentially expressed in experiments studying gastric cancer with normal gastric mucosa. AURKA is not only related to the Wnt and Akt signaling pathways but also may regulate histone modification through other ways. What’s more, MLN8237, the inhibitor of AURKA, have the effect of anti-tumor. The study provides insights into the relevance of AURKA and related genes for the progression of EMT, reveals the significance of histone modification in the progression and highlights their potential to be explorted as therapeutic targets.