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The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing

Author

Listed:
  • Xiaohui Hu

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Samuel E. Harvey

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Rong Zheng

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jingyi Lyu

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Caitlin L. Grzeskowiak

    (Baylor College of Medicine)

  • Emily Powell

    (The University of Texas MD Anderson Cancer Center)

  • Helen Piwnica-Worms

    (The University of Texas MD Anderson Cancer Center)

  • Kenneth L. Scott

    (Baylor College of Medicine)

  • Chonghui Cheng

    (Baylor College of Medicine
    Baylor College of Medicine)

Abstract

Alternative splicing has been shown to causally contribute to the epithelial–mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein–protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.

Suggested Citation

  • Xiaohui Hu & Samuel E. Harvey & Rong Zheng & Jingyi Lyu & Caitlin L. Grzeskowiak & Emily Powell & Helen Piwnica-Worms & Kenneth L. Scott & Chonghui Cheng, 2020. "The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14304-1
    DOI: 10.1038/s41467-020-14304-1
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    Cited by:

    1. Tianxin Liu & Qian Zhu & Yan Kai & Trevor Bingham & Stacy Wang & Hye Ji Cha & Stuti Mehta & Thorsten M. Schlaeger & Guo-Cheng Yuan & Stuart H. Orkin, 2024. "Matrin3 mediates differentiation through stabilizing chromatin loop-domain interactions and YY1 mediated enhancer-promoter interactions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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