Acetylation of ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion

Area of Science:

• Oncology
• Cell Biology
• Molecular Mechanisms

Background:

• Tumor metastasis is a primary driver of cancer mortality.
• Chemokine CCL18 secreted by tumor-associated macrophages is implicated in breast tumor metastasis.
• The precise molecular mechanisms underlying CCL18's role in metastasis are not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which ACAP4 regulates CCL18-induced breast cancer cell migration.
• To investigate the role of PCAF-mediated acetylation of ACAP4 in breast cancer metastasis.

Main Methods:

• Investigated the interaction between ACAP4 and PCAF using biochemical assays.
• Identified the specific acetylation site on ACAP4 using mass spectrometry.
• Utilized overexpression of acetylation-mimicking and non-acetylatable ACAP4 mutants to assess functional impact.
• Analyzed the effect of ACAP4 acetylation on its lipid-binding activity and ARF6 complex dynamics.

Main Results:

• CCL18 stimulation promotes breast cancer cell migration and invasion through PCAF-dependent acetylation of ACAP4.
• ACAP4 physically interacts with PCAF, and Lys311 is identified as the key acetylation site.
• Dynamic acetylation of ACAP4 at Lys311 is crucial for CCL18-induced cell migration and invasion.
• Acetylation of ACAP4 at Lys311 modulates its lipid-binding activity, affecting ARF6-ACAP4 complex dynamics at the plasma membrane.

Conclusions:

• ACAP4 regulates CCL18-elicited breast cancer cell migration and invasion via PCAF-mediated acetylation at Lys311.
• Dynamic acetylation of ACAP4 controls its interaction with the plasma membrane, impacting ARF6 cycling.
• This study reveals a novel mechanism involving ACAP4 acetylation in breast cancer metastasis.