Elucidation of the regulatory mechanism of HPV gene expression by host transcriptional cofactors and development of anti-HPV peptide drugs.

• Project/Area Number: 18K09244
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Mori Seiichiro 国立感染症研究所, 病原体ゲノム解析研究センター, 主任研究官 (80342898)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: パピローマウイルス / 遺伝子発現 / 転写因子 / 転写共役因子 / 子宮頸がん / ペプチド薬

Outline of Final Research Achievements

The TEAD family of transcription factors requires associating cofactors to induce gene expression. TEAD1 is known to activate the early promoter of human papillomavirus (HPV), but the precise mechanisms of TEAD1-mediated transactivation of the HPV promoter, including its relevant cofactors, remain unexplored. In this study, we revealed that VGLL1, a TEAD-interacting cofactor, contributes to HPV early gene expression. Knockdown of VGLL1 and/or TEAD1 led to a decrease in viral early gene expression in human cervical keratinocytes and cervical cancer cell lines. We identified 11 TEAD1 target sites in the HPV16 long control region (LCR). VGLL1 bound to the HPV16 LCR via its interaction with TEAD1 both in vitro and in vivo. These results suggest that multiple VGLL1/TEAD1 complexes are recruited to the LCR to support the efficient transcription of HPV early genes.

Academic Significance and Societal Importance of the Research Achievements

HPVの遺伝子発現に関わる多くの宿主転写因子が報告されているが、転写共役因子についてはほとんど知られていない。本研究で、転写共役因子VGLL1が、転写因子TEAD1を介してHPVゲノムの転写調節領域に結合し、転写を活性化することが明らかとなった。TEAD1が広範な細胞種で発現しているのに対し、VGLL1は主に上皮細胞で発現していることから、VGLL1はHPVの上皮細胞への指向性に関わる重要な宿主因子と推測される。また、shRNAを用いてVGLL1をノックダウンすると子宮頸がん細胞の増殖が抑制されたことから、VGLL1は子宮頸がん治療の標的分子となり得る。

Research Products

• [Journal Article] Transcription Factor Homeobox D9 Drives the Malignant Phenotype of HPV18-Positive Cervical Cancer Cells via Binding to the Viral Early Promoter (2021)
  • Author(s): Hayashi S, Iwata T, Imagawa R, Sugawara M, Chen G, Tanimoto S, Sugawara Y, Tanaka I, Matsui T, Nishio H, Nakamura M, Katoh Y, Mori S, Kukimoto I, Aoki D.
  • Journal Title: Cancers (Basel) Volume: 13(18) Issue: 18 Pages: 4613-4613
  • DOI: 10.3390/cancers13184613
  • Peer Reviewed / Open Access
• [Journal Article] The Transcriptional Cofactor VGLL1 Drives Transcription of Human Papillomavirus Early Genes via TEAD1 (2020)
  • Author(s): Mori S, Takeuchi T, Ishii Y, Kukimoto I.
  • Journal Title: J Virol Volume: 94 Issue: 10
  • DOI: 10.1128/jvi.01945-19
  • Peer Reviewed
• [Journal Article] Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia (2020)
  • Author(s): Baba S, Taguchi A, Kawata A, Hara K, Eguchi S, Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi A, Maeda D, Komatsu A, Nagamatsu T, Oda K, Kukimoto I, Osuga Y, Fujii T, Kawana K.
  • Journal Title: Virol J Volume: 17 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s12985-020-01306-0
  • NAID: 120007089054
  • Peer Reviewed / Open Access
• [Journal Article] Whole-Genome Analysis of Human Papillomavirus Type 16 Prevalent in Japanese Women with or without Cervical Lesions. (2019)
  • Author(s): Hirose Y, Onuki M, Tenjimbayashi Y, Yamaguchi-Naka M, Mori S, Tasaka N, Satoh T, Morisada T, Iwata T, Kiyono T, Mimura T, Sekizawa A, Matsumoto K, Kukimoto I.
  • Journal Title: Viruses Volume: 11 Issue: 4 Pages: 350-350
  • DOI: 10.3390/v11040350
  • NAID: 120007133500
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection (2019)
  • Author(s): Takeuchi F, Kukimoto I, Li Z, Li S, Li N, Hu Z, Takahashi A, Inoue S, Yokoi S, Chen J, Hang D, Kuroda M, Matsuda F, Mizuno M, Mori S, Wu P, Tanaka N, Matsuo K, Kamatani Y, Kubo M, Ma D, Shi Y.
  • Journal Title: Hum Mol Genet. Volume: 28 Issue: 2 Pages: 341-348
  • DOI: 10.1093/hmg/ddy390
  • Peer Reviewed / Int'l Joint Research
• [Presentation] TRANSCRIPTIONAL FACTOR TEAD1 AND ITS COFACTOR VGLL1 ARE REQUIRED FOR TRANSCRIPTION OF HPV16 EARLY GENES (2019)
  • Author(s): Mori S, Kukimoto I.
  • Organizer: 第67回日本ウイルス学会学術総会.
• [Presentation] 転写共役因子VGLL1による転写因子TEADを介したヒトパピローマウイルス初期遺伝子の転写 (2018)
  • Author(s): 森 清一郎、竹内 隆正、石井 克幸、柊元 巌
  • Organizer: 第66回日本ウイルス学会学術総会.
• [Presentation] TRANSCRIPTIONAL COFACTOR VGLL1 IS REQUIRED FOR TEAD-MEDIATED TRANSCRIPTION OF HPV EARLY GENES (2018)
  • Author(s): Mori S, Takeuchi T, Ishii Y, Kukikmoto I.
  • Organizer: 30th International Papillomavirus Conference
  • Int'l Joint Research