BAP1 Is a Novel Target in HPV-Negative Head and Neck Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Head and neck squamous cell carcinoma (HNSCC) presents challenges in radiotherapy.
• The role of nuclear deubiquitinating enzymes in cancer radioresistance is an area of active investigation.
• BRCA1-associated protein-1 (BAP1) is a key nuclear deubiquitinating enzyme with known roles in DNA repair and tumor suppression.

Purpose of the Study:

• To investigate the role of BAP1 in radioresistance in HNSCC.
• To determine if BAP1 expression levels correlate with radiosensitivity in HNSCC cell lines and patient outcomes.

Main Methods:

• BAP1 expression was manipulated (overexpressed, knocked down, rescued) in HNSCC cell lines (HPV-positive and HPV-negative).
• Radiosensitivity was assessed using clonogenic survival and tumor growth delay assays in vitro and in vivo (mouse xenograft model).
• Protein expression, DNA repair foci (BRCA1, γ-H2AX), and DNA repair pathways (homologous recombination, nonhomologous end joining) were analyzed. Patient data from The Cancer Genome Atlas (TCGA) HNSCC database were examined.

Main Results:

• BAP1 overexpression increased radioresistance in HNSCC cell lines and xenografts.
• BAP1 knockdown enhanced histone H2A ubiquitination, suggesting impaired DNA repair.
• BAP1 depletion suppressed homologous recombination (HR) by inhibiting BRCA1 foci formation, but did not significantly affect nonhomologous end joining (NHEJ).
• High BAP1 expression in HNSCC patients correlated with increased failure rates after radiotherapy.

Conclusions:

• BAP1 contributes to radioresistance in HNSCC, potentially by deubiquitinating histone H2A and modulating homologous recombination.
• BAP1 expression is associated with poorer outcomes in HNSCC patients treated with radiotherapy.
• BAP1 represents a potential therapeutic target for overcoming radioresistance in HNSCC.