Zhu Zhongcheng, Zhou Yuan, Chen Yongheng, Zhou Zhongyi, Liu Wenxue, Zheng Linyi, Pei Qian, Tan Fengbo, Pei Haiping, Li Yuqiang
Department of General Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, China.
Cancers (Basel). 2022 Oct 14;14(20):5025. doi: 10.3390/cancers14205025.
Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (mA), is involved in the tumorigenesis of many types of cancer. As one of the largest mA methyltransferase complex components, KIAA1429 bridges the catalytic mA 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 mA content between resistant cells and wild type cells. The mA 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 mA "reader" that interacts with mA 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.
尽管顺铂常用于治疗胃癌，但耐药性是有效治疗的主要障碍。信使核糖核酸（mRNA）修饰，即N6-甲基腺苷（m6A），参与多种癌症的肿瘤发生过程。作为最大的m6A甲基转移酶复合体成分之一，KIAA1429连接催化性m6A甲基转移酶成分，如METTL3。在胃癌中，据报道KIAA1429可促进细胞增殖。然而，KIAA1429是否参与胃癌对顺铂的耐药性尚不清楚。在此，我们构建了顺铂耐药的胃癌细胞系，并比较了耐药细胞与野生型细胞之间的m6A含量。耐药细胞中的m6A含量以及KIAA1429表达更高。有趣的是，顺铂处理后KIAA1429的表达显著增加。然后我们使用短发夹RNA（shRNA）敲低KIAA1429，发现KIAA1429缺失后耐药细胞对顺铂治疗的反应更强，而KIAA1429的过表达降低了敏感性。此外，我们在KIAA1429的启动子区域鉴定出一个假定的p65结合位点，染色质免疫沉淀（ChIP）试验证实了这种结合。p65缺失降低了KIAA1429的表达。YTHDF1是与m6A修饰的mRNA相互作用的最丰富的m6A“读取器”。从机制上讲，KIAA1429将YTHDF1招募到转录因子FOXM1的3'-非翻译区（3'-UTR）并稳定FOXM1 mRNA。更重要的是，敲低KIAA1429可增加耐药细胞在体内对顺铂的敏感性。总之，我们的结果表明，KIAA1429通过稳定胃癌细胞中的FOXM1 mRNA促进顺铂耐药。
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