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

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• Alternative splicing is implicated in epithelial-mesenchymal transition (EMT) and cancer metastasis.
• The specific splicing factors controlling these processes are not fully understood.

Purpose of the Study:

• To identify novel splicing factors involved in EMT and breast cancer metastasis.
• To investigate the role of A-Kinase Anchor Protein (AKAP8) in these processes.

Main Methods:

• Protein-protein interaction assays to study AKAP8 and hnRNPM.
• RNA binding assays to assess AKAP8's direct interaction with RNA.
• Genome-wide analysis to identify AKAP8-regulated splicing targets.
• Experimental manipulation of CLSTN1 splicing.
• Correlation analysis of AKAP8 expression and CLSTN1 splicing with patient survival data.

Main Results:

• A-Kinase Anchor Protein (AKAP8) was identified as a splicing factor that inhibits EMT and breast cancer metastasis.
• AKAP8 inhibits the splicing activity of hnRNPM via protein-protein interaction and directly alters RNA splicing.
• AKAP8 promotes an epithelial cell state splicing program.
• Alternative splicing of CLSTN1, an AKAP8 target, is critical for EMT.
• AKAP8 expression and CLSTN1 splicing predict patient survival.

Conclusions:

• AKAP8 acts as a crucial regulator of alternative splicing, suppressing EMT and metastasis.
• The splicing of CLSTN1 is a key mechanism through which AKAP8 exerts its function.
• RNA metabolism plays an essential role in metastatic breast cancer, with AKAP8 and CLSTN1 serving as potential therapeutic targets.