Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

作者：Li, SiSi; Qi, YangFan; Yu, JiaChuan; Hao, YuChao; He, Bin; Zhang, MengJuan; Dai, ZhenWei; Jiang, TongHui; Li, SuYi; Huang, Fang; Chen, Ning; Wang, Jing; Yang, MengYing; Liang, DaPeng; An, Fan; Zhao, JinYao; Fan, WenJun; Pan, YuJia; Deng, ZiQian; Luo, YuanYuan; Guo, Tao; Peng, Fei; Hou, ZhiJie; Wang, ChunLi; Zheng, FeiMeng; Xu, LingZhi; Xu, Jie; Wen, QingPing; Jin, BiLian^*; Wang, Yang^*; Liu, Quentin^*

来源：Signal Transduction and Targeted Therapy, 2022, 7(1): 97.

DOI：10.1038/s41392-022-00905-3

• MESSENGER-RNA
• FACTOR SF2/ASF
• N-MYC
• BINDING
• TRANSLATION
• TARGET
• INHIBITOR
• REGULATOR
• PROTEIN

Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m(6)A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m(6)A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m(6)A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m(6)A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

• 单位
  1; 哈尔滨医科大学; y; 中山大学