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极光激酶A调控乳腺癌中与癌症相关的RNA异常剪接。

Aurora kinase A regulates cancer-associated RNA aberrant splicing in breast cancer.

作者信息

Li Sisi, Qi Yangfan, Yu Jiachuan, Hao Yuchao, Xu Lingzhi, Ding Xudong, Zhang Minghui, Geng Jingshu

机构信息

Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China.

Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.

出版信息

Heliyon. 2023 Jun 24;9(7):e17386. doi: 10.1016/j.heliyon.2023.e17386. eCollection 2023 Jul.

DOI:10.1016/j.heliyon.2023.e17386
PMID:37415951
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10320321/
Abstract

The contribution of oncogenes to tumor-associated RNA splicing and the relevant molecular mechanisms therein require further elaboration. Here, we show that oncogenic Aurora kinase A (AURKA) promotes breast cancer-related RNA aberrant splicing in a context-dependent manner. AURKA regulated pan-breast cancer-associated RNA splicing events including GOLGA4, RBM4 and UBQLN1. Aberrant splicing of GOLGA4 and RBM4 was closely related to breast cancer development. Mechanistically, AURKA interacted with the splicing factor YBX1 and promoted AURKA-YBX1 complex-mediated GOLGA4 exon inclusion. AURKA binding to the splicing factor hnRNPK promoted AURKA-hnRNPK complex-mediated RBM4 exon skipping. Analysis of clinical data identified an association between the AURKA-YBX1/hnRNPK complex and poor prognosis in breast cancer. Blocking AURKA nuclear translocation with small molecule drugs partially reversed the oncogenic splicing of RBM4 and GOLGA4 in breast cancer cells. In summary, oncogenic AURKA executes its function on modulating breast cancer-related RNA splicing, and nuclear AURKA is distinguished as a hopeful target in the case of treating breast cancer.

摘要

致癌基因对肿瘤相关RNA剪接的贡献及其相关分子机制仍需进一步阐明。在此，我们表明致癌性极光激酶A（AURKA）以上下文依赖的方式促进乳腺癌相关的RNA异常剪接。AURKA调控泛乳腺癌相关的RNA剪接事件，包括高尔基体蛋白A4（GOLGA4）、RNA结合蛋白4（RBM4）和泛素样蛋白1（UBQLN1）。GOLGA4和RBM4的异常剪接与乳腺癌发展密切相关。机制上，AURKA与剪接因子Y盒结合蛋白1（YBX1）相互作用，并促进AURKA-YBX1复合物介导的GOLGA4外显子包含。AURKA与剪接因子不均一核糖核蛋白K（hnRNPK）结合促进AURKA-hnRNPK复合物介导的RBM4外显子跳跃。临床数据分析确定了AURKA-YBX1/hnRNPK复合物与乳腺癌预后不良之间的关联。用小分子药物阻断AURKA核转位可部分逆转乳腺癌细胞中RBM4和GOLGA4的致癌剪接。总之，致癌性AURKA在调节乳腺癌相关RNA剪接方面发挥作用，并且核AURKA有望成为治疗乳腺癌的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/2dc629c7229e/mmcfigs20.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/068b0c522f74/gr1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/5b7fbb70c27b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/cbdcdefd08b9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/1dede30cea30/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/a9a13ad712fa/mmcfigs1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/8483a6137cd0/mmcfigs10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/15878882aff0/mmcfigs11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/c3018229d157/mmcfigs12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/d8fd45133096/mmcfigs13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/aaa604a23544/mmcfigs14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/55ae84552ff3/mmcfigs15.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/5ab6367d2ccd/mmcfigs16.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/8745c2adfb64/mmcfigs17.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/32397236ebe8/mmcfigs18.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/2dc629c7229e/mmcfigs20.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/068b0c522f74/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/314355563cbf/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/5b7fbb70c27b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/cbdcdefd08b9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/1dede30cea30/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/a9a13ad712fa/mmcfigs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/cd955b47edb8/mmcfigs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/22b620b43ad7/mmcfigs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/1bf0fbedecba/mmcfigs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/42caee0172c9/mmcfigs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/ac5f27260bca/mmcfigs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/6528d582fca4/mmcfigs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/de3770e65e07/mmcfigs8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/eae2b28c43b1/mmcfigs9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/8483a6137cd0/mmcfigs10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/15878882aff0/mmcfigs11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/c3018229d157/mmcfigs12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/d8fd45133096/mmcfigs13.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/aaa604a23544/mmcfigs14.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/55ae84552ff3/mmcfigs15.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/5ab6367d2ccd/mmcfigs16.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/8745c2adfb64/mmcfigs17.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/32397236ebe8/mmcfigs18.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4070/10320321/2dc629c7229e/mmcfigs20.jpg

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