m(6)A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA

SIMPLE SUMMARY: N6-methyladenosine (m(6)A) is involved in the development of drug resistance in various cancer types. The role of N6-methyladenosine (m(6)A) methyltransferase, KIAA1429, in the resistance of gastric cancer to cisplatin is largely unknown. In this study, the KIAA1429 expression level as well as m(6)A content were found to be higher in cisplatin resistant gastric cancer cells, and KIAA1429 regulated the sensitivity of gastric cancer cells to cisplatin treatment. We then identified p65 as the regulator of KIAA1429 expression. Mechanistically, KIAA1429 regulated the sensitivity of gastric cancer cells to cisplatin by stabilizing FOXM1 mRNA via YTHDF1. The findings from this study suggest that KIAA1429 could be a therapeutic target of cisplatin resistance in gastric cancer. ABSTRACT: Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m(6)A), is involved in the tumorigenesis of many types of cancer. As one of the largest m(6)A methyltransferase complex components, KIAA1429 bridges the catalytic m(6)A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m(6)A content between resistant cells and wild type cells. The m(6)A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m(6)A “reader” that interacts with m(6)A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3′-untranslated Region (3′-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.