American Association for Cancer Research
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Figure S2 from Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

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posted on 2023-03-31, 20:10 authored by Asel Biktasova, Michael Hajek, Andrew Sewell, Cyril Gary, Gary Bellinger, Hari A. Deshpande, Aarti Bhatia, Barbara Burtness, Benjamin Judson, Saral Mehra, Wendell G. Yarbrough, Natalia Issaeva

DNMT1, p53, phospho-p53 Ser15 and gamma H2AX levels in UMSCC47 cells treated with 5-aza or zeocin for 48 hours. Actin was used as a loading control



Purpose: DNA methylation in human papillomavirus–associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels.Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276–87. ©2017 AACR.

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