A TGF-β-responsive enhancer regulates SRC expression and epithelial-mesenchymal transition-associated cell migration.

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Signaling

Background:

• Non-receptor tyrosine kinase SRC is overexpressed in cancers, driving invasion and metastasis.
• Mechanisms of SRC upregulation in cancer remain largely unknown.

Purpose of the Study:

• To elucidate the mechanisms by which transforming growth factor-beta (TGF-β) induces SRC expression.
• To investigate the role of TGF-β-induced SRC upregulation in cancer progression.

Main Methods:

• Utilized MCF10A human breast epithelial cells for TGF-β1 stimulation.
• Performed chromatin immunoprecipitation (ChIP)-sequencing to identify enhancer regions.
• Analyzed the role of SMAD and JUN in regulating SRC expression.

Main Results:

• TGF-β induces SRC expression transcriptionally by activating an intragenic SRC enhancer.
• TGF-β1 upregulates the SRC 1A promoter, increasing SRC mRNA and protein.
• SMAD complex and JUN are recruited to SRC enhancers, mediating TGF-β-induced SRC expression.
• TGF-β-induced SRC upregulation activates the SRC-FAK circuit, promoting EMT-associated cell migration.

Conclusions:

• TGF-β signaling drives SRC upregulation through enhancer activation, contributing to cancer cell invasion and metastasis.
• The identified TGF-β-SRC pathway is a potential therapeutic target for specific human malignancies.