PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Alternative splicing (AS) dysregulation is crucial in cancer, but its role in breast cancer remains unclear.
• RNA-binding proteins are key regulators of AS, influencing tumor development.
• Identifying specific splicing factors involved in breast cancer progression is essential.

Purpose of the Study:

• To investigate the role of RNA-binding proteins in breast cancer development.
• To identify key splicing factors contributing to breast cancer progression.
• To elucidate the molecular mechanisms underlying PHF5A's function in breast cancer.

Main Methods:

• Conducted an in vivo CRISPR screen targeting RNA-binding proteins.
• Assessed PHF5A expression in breast cancer specimens.
• Performed knockdown experiments to evaluate PHF5A's functional impact.
• Investigated the interaction of PHF5A with the SF3b spliceosome and histones.
• Analyzed the PHF5A-FASTK axis in breast cancer samples.

Main Results:

• PHD finger protein 5A (PHF5A) was identified as a critical splicing factor in breast cancer.
• PHF5A is upregulated in breast cancer, correlating with poor survival.
• PHF5A knockdown suppressed tumor cell proliferation, migration, and formation.
• PHF5A stabilizes the SF3b spliceosome and influences alternative splicing of apoptotic genes.
• PHF5A ablation increased truncated FASTK, enhancing Fas-mediated apoptosis.

Conclusions:

• PHF5A acts as an epigenetic suppressor of apoptosis, driving breast cancer progression.
• The PHF5A-modulated FASTK-AS axis is prevalent in breast cancer, especially triple-negative subtypes.
• PHF5A represents a potential therapeutic target for breast cancer treatment.