PBRM1-dependent PBAF targeting is required for EMT and metastasis in breast cancer

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• SWI/SNF chromatin remodelers regulate gene expression through distinct subcomplexes like PBAF.
• PBAF's role in chromatin regulation and gene activation, particularly in disease, remains incompletely understood.
• Previous genetic studies highlighted PBAF's importance in development and disease.

Purpose of the Study:

• To investigate the role of the PBAF chromatin remodeler, specifically its PBRM1 subunit, in TGFβ1-mediated epithelial-mesenchymal transition (EMT) and breast cancer metastasis.
• To elucidate the molecular mechanisms by which PBAF influences gene activation during EMT and cancer progression.

Main Methods:

• Epigenomic profiling (e.g., H3K14ac, DNA accessibility) at different stages of EMT.
• In vitro studies using mammary cells undergoing TGFβ1-induced EMT.
• In vivo studies involving murine breast cancer metastasis models.
• Analysis of transcription factor binding (e.g., Atf3) and gene induction.

Main Results:

• The PBRM1 subunit of PBAF is essential for completing TGFβ1-induced EMT in mammary cells and for breast cancer metastasis in vivo.
• PBRM1 directs PBAF binding to inducible promoters marked by H3K14ac during EMT.
• PBRM1 enhances DNA accessibility at transcription factor binding sites, promoting the induction of genes involved in cell migration, survival, and inflammation.

Conclusions:

• PBAF, through its PBRM1 subunit, plays a critical role in driving key processes of EMT and cancer metastasis.
• PBAF's function in targeting inducible promoters and facilitating gene activation highlights its significance in late-stage metastatic cancers.
• PBAF represents a potential therapeutic vulnerability in advanced metastatic breast cancer.