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

Nat Commun. 2020 Jan 24;11(1):486. doi: 10.1038/s41467-020-14304-1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / antagonists & inhibitors
  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Alternative Splicing / genetics*
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group M / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group M / metabolism
  • Heterografts
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Protein Interaction Domains and Motifs
  • RNA / genetics
  • RNA / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism


  • A Kinase Anchor Proteins
  • AKAP8 protein, human
  • CLSTN1 protein, human
  • Calcium-Binding Proteins
  • HNRNPM protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group M
  • RNA-Binding Proteins
  • RNA