Senataxin regulates cisplatin resistance through an R-loop-mediated mechanism in HPV-associated head and neck cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cisplatin resistance is a major challenge in treating head and neck cancers, both HPV-independent and HPV-associated.
• DNA repair mechanisms, particularly those addressing endogenous DNA damage like R-loops (DNA/RNA hybrids), are implicated in this resistance.

Purpose of the Study:

• To investigate the role of R-loops and their regulators in cisplatin resistance in head and neck cancer cell lines.
• To explore senataxin as a potential therapeutic target in HPV-associated cisplatin-resistant head and neck cancer.

Main Methods:

• Development of HPV-positive and HPV-negative cisplatin-resistant head and neck cancer cell lines.
• RNA-sequencing to identify alterations in R-loop regulator expression.
• Senataxin depletion experiments to assess its impact on cisplatin sensitivity, DNA damage, and R-loop levels.

Main Results:

• Resistant cell lines exhibited elevated global R-loop levels.
• HPV-positive resistant cells showed increased expression of senataxin, a protein that resolves R-loops.
• Depleting senataxin in HPV-positive cells increased cisplatin sensitivity, DNA damage, and R-loop accumulation.

Conclusions:

• Senataxin modulates cisplatin sensitivity in HPV-positive head and neck cancer via an R-loop-dependent mechanism.
• R-loops represent a promising therapeutic target for overcoming cisplatin resistance in these cancers.
• Further research into senataxin and R-loops is warranted for clinical applications.