Elucidation of the molecular mechanism of carcinogenesis by chromatin structure analysis of HPV-associated head and neck squamous cell carcinoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K18271
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Chiba University
• Principal Investigator: Mima Masato 千葉大学, 大学院医学研究院, 特任助教 (40866109)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 頭頸部扁平上皮癌 / Human papillomavirus / がんエピゲノム / ヒストン修飾 / クロマチン構造

Outline of Final Research Achievements

Human papillomavirus (HPV) is involved in the development of head and neck squamous cell carcinoma (HNSCC). To elucidate involvement of epigenetic dysregulation in tumorigenesis, we performed integrated analyses of the epigenome, transcriptome and interactome using ChIP-seq, RNA-seq and Hi-C and 4C-seq for HPV(+) HNSCCs. In HPV(+) HNSCC cell line UPCI-SCC-090, 4C-seq revealed 0.5 to 40 Mb of HPV-interacting regions (HPVIRs) where host genomic regions interacted with integrated HPV genomes. The non-amplified HPVIRs were found to show a significant increase in H3K27ac levels and an upregulation of genes associated with signaling by WNT. Among those genes, ITPR3 was significantly upregulated　by UPCI-SCC-090-specific super-enhancer formation. The knockdown of ITPR3 by siRNA or CRISPR deletions of the enhancer region led to a significant suppression of cell proliferation. These data indicate that epigenetic activation in HPVIRs contributes, at least partially, to genesis of HPV(+) HNSCC.

Free Research Field

頭頸部悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

本研究ではITPR3のノックダウンによる頭頸部扁平上皮癌細胞の増殖抑制に加えて、エンハンサー領域を削除するゲノム編集によってITPR3の発現抑制、細胞増殖の抑制を明らかとした。このことから、ITPR3タンパク質だけでなく、ITPR3遺伝子のエンハンサー領域を標的とするエピゲノムの観点から治療戦略に繋がる新規知見を得られたことに学術的意義が高いと考える。実際、ゲノム編集技術の臨床応用については様々な疾患で治験が進行中であり、HPV陽性頭頸部扁平上皮癌においてもこうした技術が個別化医療の構築へ寄与する社会的意義を有しているものと考えられる。