Tumorigenic activation around HPV integrated sites in head and neck squamous cell carcinoma. Issue 9 (7th February 2023)

• Record Type: Journal Article
• Authors: Mima, Masato; Okabe, Atsushi; Hoshii, Takayuki; Nakagawa, Takuya; Kurokawa, Tomoya; Kondo, Satoru; Mizokami, Harue; Fukuyo, Masaki; Fujiki, Ryoji; Rahmutulla, Bahityar; Yoshizaki, Tomokazu; Hanazawa, Toyoyuki; Misawa, Kiyoshi; Kaneda, Atsushi
• Is Part Of: International journal of cancer. Volume 152:Issue 9(2023)
• Page Start: 1847
• Page End: 1862
• Publication Date: 2023-02-07
• Subjects: epigenome -- head and neck squamous cell carcinoma -- HPV‐interacting regions -- human papillomavirus; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34439
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Human papillomavirus (HPV) is causally involved in the development of head and neck squamous cell carcinoma (HNSCC). The integration of HPV drives tumorigenesis through expression of oncogenic viral genes as well as genomic alterations in surrounding regions. To elucidate involvement of epigenetic dysregulation in tumorigenesis, we here performed integrated analyses of the epigenome, transcriptome and interactome using ChIP‐seq, RNA‐seq and Hi‐C and 4C‐seq for HPV(+) HNSCCs. We analyzed clinical HNSCC using The Cancer Genome Atlas data and found that genes neighboring HPV integration sites were significantly upregulated and were correlated with oncogenic phenotypes in HPV(+) HNSCCs. While we found four HPV integration sites in HPV(+) HNSCC cell line UPCI‐SCC‐090 through target enrichment sequencing, 4C‐seq revealed 0.5 to 40 Mb of HPV‐interacting regions (HPVIRs) where host genomic regions interacted with integrated HPV genomes. While 9% of the HPVIRs were amplified and activated epigenetically forming super‐enhancers, the remaining non‐amplified regions were found to show a significant increase in H3K27ac levels and an upregulation of genes associated with GO terms, for example, Signaling by WNT and Cell Cycle. Among those genes, ITPR3 was significantly upregulated, involving UPCI‐SCC‐090‐specific super‐enhancer formation around the ITPR3 promoter and in the 80‐kb‐downstream region. The knockdown of ITPR3 by siRNA or CRISPR deletions of the distant enhancer region led to a significant suppression of cell proliferation. The epigenetic activation of HPVIRs was also confirmed in other cell lines, UM‐SCC‐47 and UM‐SCC‐104. These data indicate that epigenetic activation in HPVIRs contributes, at least partially, to genesis of HPV(+) HNSCC. Abstract : What's new? Human papillomavirus (HPV) causes cancer by integrating its genetic material into the host cell's genome. Cancer may result from viral oncogenes becoming active or by disruptions in the surrounding regions. Here, the authors investigated how epigenetic dysregulation plays a part in tumorigenesis. They analyzed HPV+ head and neck squamous cell carcinomas (HNSCC) looking for regions that interact with HPV and identifying their epigenetic status. They found that in HPV‐interacting regions, genes associated with oncogenic signals were epigenetically upregulated, suggesting a mechanism for HSNCC onset as well as a possible therapeutic strategy.