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p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade. Cancer research Molkentine, D. P., Molkentine, J. M., Bridges, K. A., Valdecanas, D. R., Dhawan, A., Bahri, R., Hefner, A. J., Kumar, M., Yang, L., Abdelhakiem, M., Pifer, P. M., Sandulache, V., Sheth, A., Beadle, B. M., Thames, H. D., Mason, K. A., Pickering, C. R., Meyn, R. E., Skinner, H. D. 1800

Abstract

Squamous cell carcinoma driven by human papillomavirus (HPV) is more sensitive to DNA-damaging therapies than its HPV-negative counterpart. Here we show that p16, the clinically utilized surrogate for HPV positivity, renders cells more sensitive to radiation via a ubiquitin-dependent signaling pathway, linking high levels of this protein to increased activity of the transcription factor SP1, increased HUWE1 transcription, and degradation of ubiquitin-specific protease 7 (USP7) and TRIP12. Activation of this pathway in HPV-positive disease led to decreased homologous recombination (HR) and improved response to radiation, a phenomenon that can be recapitulated in HPV-negative disease using USP7 inhibitors in clinical development. This p16-driven axis induced sensitivity to PARP inhibition and potentially leads to "BRCAness" in head and neck squamous cell carcinoma (HNSCC) cells. Thus, these findings support a functional role for p16 in HPV-positive tumors in driving response to DNA damage, which can be exploited to improve outcomes in both HPV-positive and HPV-negative HNSCC patients.

View details for DOI 10.1158/0008-5472.CAN-21-2101

View details for PubMedID 34965932