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仍不清楚。目前的研究重点是 m6A writer KIAA1429 在肿瘤发展中的潜在功能以及肝癌中索拉非尼的敏感性。我们发现肝癌组织和细胞中KIAA1429的水平显着升高，并且与较差的预后密切相关。在功能上，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影响最大的途径之一，而m6A修饰的HK1是最有可能调节Warburg效应的靶基因。 KIAA1429 耗尽会降低肝癌中的 Warburg 效应并增加索拉非尼的敏感性。从机制上讲，KIAA1429可以通过直接与HK1 mRNA结合来影响HK1 mRNA的m6A水平。此外，KIAA1429与m6A阅读器HuR配合增强HK1 mRNA稳定性，从而上调其表达。这些研究结果表明，KIAA1429/HK1轴通过调节Warburg效应降低肝癌细胞对索拉非尼的敏感性，这可能为肝癌治疗提供新的治疗靶点。版权所有©2024。由Elsevier Inc.出版。

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.Copyright © 2024. Published by Elsevier Inc.