c-Src/histone deacetylase 3 interaction is crucial for hepatocyte growth factor dependent decrease of CXCR4...

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Hepatocyte growth factor (HGF) is a key cytokine in the tumor microenvironment.
• CXCR4 receptor expression is critical for cancer cell migration and metastasis.
• HGF exhibits differential effects on CXCR4 expression in breast cancer cells with varying invasiveness.

Purpose of the Study:

• To elucidate the distinct molecular mechanisms underlying HGF-mediated CXCR4 expression in low (MCF-7) versus highly (MDA-MB231) invasive breast carcinoma cells.
• To investigate the role of c-Src activation and its downstream effectors in regulating CXCR4 expression.

Main Methods:

• Utilized CXCR4 promoter constructs in transfected MCF-7 and MDA-MB231 cells.
• Administered HGF and/or co-transfected with c-Src wild-type (Srcwt) expression vectors.
• Assessed activation of transcription factors Ets1 and nuclear factor-kappaB (NF-kappaB).
• Investigated the interaction between c-Src and histone deacetylase 3 (HDAC3) using co-immunoprecipitation and subcellular localization studies.

Main Results:

• HGF treatment and Srcwt expression enhanced phospho-c-Src formation in both cell lines.
• In MCF-7 cells, HGF/Srcwt activated CXCR4, Ets1, and NF-kappaB.
• In MDA-MB231 cells, HGF/Srcwt decreased CXCR4, Ets1, and NF-kappaB activities.
• HDAC3 was upregulated, localized with phospho-c-Src, and co-immunoprecipitated with it in MDA-MB231 cells, suggesting its role in suppressing transcription factors.

Conclusions:

• HGF differentially regulates CXCR4 expression in breast cancer cells via distinct c-Src downstream pathways.
• In low-invasive cells, HGF/c-Src enhances CXCR4 via NF-kappaB and Ets1, potentially promoting homing.
• In highly invasive cells, HGF/c-Src-mediated HDAC3 activation suppresses CXCR4, possibly retaining cells at metastatic sites.