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

Authors

David P Molkentine
Jessica M Molkentine
Kathleen A Bridges
David R Valdecanas
Annika Dhawan
Reshub Bahri
Andrew J Hefner
Manish Kumar
Liangpeng Yang
Mohamed Abdelhakiem
Phillip M Pifer
Vlad Sandulache
Aakash Sheth
Beth M Beadle
Howard D Thames
Kathryn A Mason
Curtis R Pickering
Raymond E Meyn
Heath D Skinner

Publication Date

3-1-2022

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-21-2101

PMID

34965932

PMCID

PMC9136619

PubMedCentral® Posted Date

3-3-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Carcinoma, Squamous Cell, Carrier Proteins, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, DNA, Viral, Head and Neck Neoplasms, Humans, Papillomaviridae, Papillomavirus Infections, Signal Transduction, Squamous Cell Carcinoma of Head and Neck, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitin-Specific Peptidase 7

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 used surrogate for HPV positivity, renders cells more sensitive to radiotherapy 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 and improved response to radiotherapy, 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 patients with HPV-positive and HPV-negative HNSCC.

SIGNIFICANCE: In HPV-positive tumors, a previously undiscovered pathway directly links p16 to DNA damage repair and sensitivity to radiotherapy via a clinically relevant and pharmacologically targetable ubiquitin-mediated degradation pathway.