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

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

Cancer research (2021-12-31)
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
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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
UM-SCC-47 HPV-16 Positive Squamous Carcinoma Cell Line, UM-SCC-47 is a unique head and neck squamous carcinoma (HNSCC) cell line isolated from the primary tumor of the lateral tongue of a male patient and is a suitable in vitro model of H&N carcinoma studies. The cell line contains 18 copies of integrated HPV-16.
Sigma-Aldrich
UM-SCC-1 Squamous Carcinoma Cell Line, UM-SCC-1 is a unique human head and neck squamous cell carcinoma (HNSCC) cell line isolated from a tumor located on the floor of the mouth of a male patient and is a suitable in vitro model of H&N carcinoma studies.
Sigma-Aldrich
Anti-Actin Antibody, clone C4, ascites fluid, clone C4, Chemicon®