Hypermethylation of nc886 in HPV-positive oropharyngeal cancer and its clinical implications: An epigenome-wide association study

Yifan Xu; Ziqiao Wang; Peng Wei; Richa Gairola; Karl T Kelsey; Andrew G Sikora; Guojun Li; Jian Gu

doi:10.1016/j.omtn.2022.11.012

Hypermethylation of nc886 in HPV-positive oropharyngeal cancer and its clinical implications: An epigenome-wide association study

Mol Ther Nucleic Acids. 2022 Nov 17:30:596-605. doi: 10.1016/j.omtn.2022.11.012. eCollection 2022 Dec 13.

Authors

Yifan Xu¹, Ziqiao Wang², Peng Wei², Richa Gairola³, Karl T Kelsey^{3

4}, Andrew G Sikora^{5

6}, Guojun Li⁵, Jian Gu¹

Affiliations

¹ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Epidemiology, Brown University School of Public Health, Providence, RI 02912, USA.
⁴ Pathology and Laboratory Medicine, Brown University School of Public Health, Providence, RI 02912, USA.
⁵ Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Abstract

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased rapidly in the United States, driven by rising human papillomavirus (HPV) infections in the U.S. population. HPV-positive OPSCC patients have a better prognosis than HPV-negative patients. To gain insights into the unique biology of HPV(+) OPSCC that may contribute to its clinical behaviors, we performed a multi-stage epigenome-wide methylation profiling of leukocyte and tumor DNA in OPSCC patients and compared the methylation levels of CpG sites between HPV(+) and HPV(-) OPSCC patients. We identified and validated a significantly differentially methylated region (DMR) of 1,355 bp encompassing non-coding RNA 886 (nc886) gene and its promoter region. Nc886 is hypermethylated in both leukocytes and tumor DNA of HPV(+) OPSCC patients. Homozygous knockout of nc886 by CRISPR-Cas9 in head and neck cell lines was lethal, but nc886 could be knocked out on the background of protein kinase R (PKR) knockout. Our data suggest that HPV induces nc886 hypermethylation, and nc886 acts as both a viral sensor and a tumor sensor in OPSCC patients and contribute to the better prognosis of HPV(+) OPSCC patients. Nc886 may become a therapeutic target in OPSCC.

Keywords: DNA methylation; HPV; MT: Non-coding RNAs; OPSCC; PKR; leukocyte; nc886; non-coding RNA; oropharyngeal cancer.

Grants and funding

R01 CA236859/CA/NCI NIH HHS/United States