International journal of biological sciences · 2026
ALYREF-mediated m5C modification of CCNA1 drives escape from cell-cycle arrest and contributes to pazopanib resistance in Renal Cell Carcinoma.
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Lu Zeyi, Li Yang, Zhu Ziwei, Li Fan, Ding Yiming, Ding Lifeng, Wang Ruyue, Lin Yudong, Luo Wenqin, Mao Xudong, Lu Haohua, Wang Yejinpeng, Li Mengxuan, Chen Yuanlei, Xu Zhehao, Lu Yi, Zheng Qiming, Xie Haiyun, Zhou Zhenwei, Xia Liqun, Li Gonghui, Wang Mingchao
Аннотация
Pazopanib, a first-line tyrosine kinase inhibitor for advanced renal cell carcinoma (RCC), faces significant clinical limitations due to acquired resistance. In this study, we reveal a novel mechanism underlying pazopanib resistance in RCC, driven by a senescence-like phenotype without cell-cycle arrest. Transcriptomic profiling identified ALYREF as a key upregulated m5C reader in pazopanib resistant cells. Mechanistically, ALYREF stabilizes CCNA1 mRNA via m5C modification, promoting Cyclin A1 expression. The Cyclin A1-CDK2 complex phosphorylates p21 at Thr-57, inducing its cytoplasmic translocation and abrogating its inhibitory effect on cell cycle progression, thereby facilitating G1-S transition. Our findings uncover a critical ALYREF-Cyclin A1-p21 axis in RCC and suggest that targeting this pathway may provide novel therapeutic strategies to overcome pazopanib resistance.