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Tumorigenic activation around HPV integrated sites in head and neck squamous cell carcinoma.
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.
Affiliation
  • Mima M; Department of Otorhinolaryngology, Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
  • Okabe A; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Hoshii T; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Nakagawa T; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Kurokawa T; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Kondo S; Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Mizokami H; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Fukuyo M; Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Fujiki R; Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
  • Rahmutulla B; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Yoshizaki T; Division of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
  • Hanazawa T; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Misawa K; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Kaneda A; Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Int J Cancer ; 152(9): 1847-1862, 2023 05 01.
Article in En | MEDLINE | ID: mdl-36650703
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Squamous Cell / Papillomavirus Infections / Head and Neck Neoplasms Limits: Humans Language: En Journal: Int J Cancer Year: 2023 Type: Article Affiliation country: Japan

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Squamous Cell / Papillomavirus Infections / Head and Neck Neoplasms Limits: Humans Language: En Journal: Int J Cancer Year: 2023 Type: Article Affiliation country: Japan