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

Xiaohui Hu, Samuel E. Harvey, Rong Zheng, Jingyi Lyu, Caitlin L. Grzeskowiak, Emily Powell, Helen Piwnica-Worms, Kenneth L. Scott and Chonghui Cheng ()
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Xiaohui Hu: Baylor College of Medicine
Samuel E. Harvey: Baylor College of Medicine
Rong Zheng: Baylor College of Medicine
Jingyi Lyu: 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

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14304-1

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