Abstract：
N6-methyladenosine (m6A) serves as the most abundant posttranscription modification. However, the role of m6A in tumorigenesis and chemotherapeutic drugs sensitivity remains largely unclear. Present research focuses on the potential function of the m6A writer KIAA1429 in tumor development and sorafenib sensitivity in liver cancer. We found that the level of KIAA1429 was significantly elevated in liver cancer tissues and cells and was closely associated with poorer prognosis. Functionally, KIAA1429 promoted the proliferation and Warburg effect of liver cancer cells in vitro and in vivo. RNA-seq and MeRIP-seq analysis revealed the glycolysis was one of the most affected pathways by KIAA1429, and m6A-modified HK1 was the most likely targeted gene to regulate the Warburg effect. KIAA1429 depletion decreased Warburg effect and increased sorafenib sensitivity in liver cancer. Mechanistically, KIAA1429 could affect the m6A level of HK1 mRNA through directly binding with it. Moreover, KIAA1429 cooperated with the m6A reader HuR to enhance HK1 mRNA stability, thereby upregulating its expression. These findings demonstrated that KIAA1429/HK1 axis decreases the sensitivity of liver cancer cells to sorafenib by regulating the Warburg effect, which may provide a novel therapeutic target for liver cancer treatment.
摘要：
N6-甲基腺苷(m6A)是最丰富的转录后修饰。然而,m6A在肿瘤发生和化疗药物敏感性中的作用尚不清楚。目前的研究集中在m6A作者KIAA1429在肝癌的肿瘤发生和索拉非尼敏感性中的潜在功能。我们发现肝癌组织和细胞中KIAA1429的水平显着升高，并且与预后较差密切相关。功能上,KIAA1429在体外和体内促进肝癌细胞的增殖和Warburg效应。RNA-seq和MeRIP-seq分析显示糖酵解是KIAA1429受影响最大的途径之一，而m6A修饰的HK1是最可能调节Warburg效应的靶向基因。KIAA1429耗竭降低了Warburg效应并增加了索拉非尼在肝癌中的敏感性。机械上,KIAA1429可能通过与HK1mRNA直接结合而影响其m6A水平。此外，KIAA1429与m6A阅读器HuR合作以增强HK1mRNA的稳定性，从而提高其表达。这些发现表明，KIAA1429/HK1轴通过调节Warburg效应降低了肝癌细胞对索拉非尼的敏感性，这可能为肝癌的治疗提供新的治疗靶点。
