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

Abstract

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 m6A 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 m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-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 m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

• Authors: SiSi Li, YangFan Qi, JiaChuan Yu, YuChao Hao, Bin He, MengJuan Zhang, ZhenWei Dai, TongHui Jiang, SuYi Li, Fang Huang, Ning Chen, Jing Wang, MengYing Yang, DaPeng Liang, Fan An, JinYao Zhao, WenJun Fan, YuJia Pan, ZiQian Deng, YuanYuan Luo, Tao Guo, Fei Peng, ZhiJie Hou, ChunLi Wang, FeiMeng Zheng, LingZhi Xu, Jie Xu, QingPing Wen, BiLian Jin, Yang Wang, Quentin Liu
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 7 Issue 1 Pg. 97 (04 01 2022) ISSN: 2059-3635 [Electronic] England
• PMID: 35361747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Nerve Tissue Proteins
• RNA Splicing Factors
• RNA-Binding Proteins
• Aurora Kinase A

Topics

• Alternative Splicing
• Aurora Kinase A (genetics, metabolism)
• Cell Nucleus (genetics)
• Nerve Tissue Proteins (genetics, metabolism)
• RNA Splicing
• RNA Splicing Factors (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)