Journal Article

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

Grzeskowiak, Caitlin L., Zheng, Rong, Harvey, Samuel E., Powell, Emily, Piwnica-Worms, Helen, Hu, Xiaohui, Lyu, Jingyi, Cheng, Chonghui, Scott, Kenneth L.

2020

Overview

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. Splice isoform switching regulated by the heterogeneous nuclear ribonucleoprotein M (hnRNPM) induces EMT and metastasis. Here, the authors report that AKAP8 is a metastasis suppressor that inhibits the splicing activity of hnRNPM and antagonizes genome-wide EMT-associated alternative splicing to maintain epithelial cell state.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 38 / 38/109 / 38/88 / 38/89 / 38/90 / 38/91 / 59/5 / 631/337 / 631/67 / 64/60 / A Kinase Anchor Proteins - antagonists & inhibitors / A Kinase Anchor Proteins - genetics / A Kinase Anchor Proteins - metabolism / Alternative splicing / Alternative Splicing - genetics / Animals / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cell Line, Tumor / Epithelial cells / Epithelial-Mesenchymal Transition - genetics / Female / Gene Knockdown Techniques / Genomes / HCT116 Cells / HEK293 Cells / Heterogeneous-Nuclear Ribonucleoprotein Group M - genetics / Heterogeneous-Nuclear Ribonucleoprotein Group M - metabolism / Heterografts / Humanities and Social Sciences / Humans / Kinases / Lung Neoplasms - genetics / Lung Neoplasms - prevention & control / Lung Neoplasms - secondary / Mesenchyme / Metastases / Metastasis / Mice / Mice, Nude / multidisciplinary / Protein Interaction Domains and Motifs / Proteins / Ribonucleic acid / RNA / RNA - genetics / RNA - metabolism / RNA-binding protein / RNA-Binding Proteins - antagonists & inhibitors / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Splicing / Splicing factors / Switching / Tumors