p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Human papillomavirus (HPV)-positive squamous cell carcinoma (SCC) exhibits greater sensitivity to DNA-damaging therapies compared to HPV-negative SCC.
• p16 is a widely used clinical marker for HPV positivity in SCC.
• The underlying molecular mechanisms driving this differential sensitivity remain incompletely understood.

Purpose of the Study:

• To elucidate the functional role of p16 in mediating sensitivity to DNA-damaging therapies in SCC.
• To identify the specific signaling pathways involved in p16-driven therapeutic response.
• To explore therapeutic strategies targeting this pathway for both HPV-positive and HPV-negative HNSCC.

Main Methods:

• Investigated the role of p16 in radiosensitivity using cellular and molecular biology techniques.
• Analyzed ubiquitin-dependent signaling pathways, including transcription factor activity (SP1) and protein degradation (USP7, TRIP12).
• Assessed the impact of p16 pathway activation on DNA repair mechanisms (homologous recombination) and drug sensitivity (PARP inhibitors).

Main Results:

• p16 expression in SCC cells increases SP1 activity, HUWE1 transcription, and promotes degradation of USP7 and TRIP12 via a ubiquitin-dependent pathway.
• This p16-driven pathway decreases homologous recombination, enhancing sensitivity to radiotherapy.
• The pathway's effects, including inducing a "BRCAness" phenotype and sensitivity to PARP inhibition, can be mimicked in HPV-negative SCC using USP7 inhibitors.

Conclusions:

• p16 plays a crucial functional role in HPV-positive HNSCC by linking HPV status to enhanced sensitivity to DNA-damaging agents like radiotherapy and PARP inhibitors.
• The identified ubiquitin-mediated signaling axis is a key determinant of therapeutic response in HNSCC.
• Targeting USP7 offers a promising strategy to sensitize both HPV-positive and HPV-negative HNSCC to DNA-damaging therapies, improving patient outcomes.