Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus

Michelle Khattri, Yutaka Amako, Julia R. Gibbs, Joseph L. Collura, Reety Arora, Alexis Harold, Meng Yen Li, Paul W. Harms, Elena Ezhkova, Masahiro Shuda

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Merkel cell polyomavirus (MCV) and high-risk human papillomavirus (HPV) are human tumor viruses that cause Merkel cell carcinoma (MCC) and oropharyngeal squamous cell carcinoma (OSCC), respectively. HPV E7 and MCV large T (LT) oncoproteins target the retinoblastoma tumor suppressor protein (pRb) through the conserved LxCxE motif. We identified enhancer of zeste homolog 2 (EZH2) as a common host oncoprotein activated by both viral oncoproteins through the pRb binding motif. EZH2 is a catalytic subunit of the polycomb 2 (PRC2) complex that trimethylates histone H3 at lysine 27 (H3K27me3). In MCC tissues EZH2 was highly expressed, irrespective of MCV status. Loss-of-function studies revealed that viral HPV E6/E7 and T antigen expression are required for Ezh2 mRNA expression and that EZH2 is essential for HPV(+)OSCC and MCV(+)MCC cell growth. Furthermore, EZH2 protein degraders reduced cell viability efficiently and rapidly in HPV(+)OSCC and MCV(+)MCC cells, whereas EZH2 histone methyltransferase inhibitors did not affect cell proliferation or viability within the same treatment period. These results suggest that a methyltransferase-independent function of EZH2 contributes to tumorigenesis downstream of two viral oncoproteins, and that direct targeting of EZH2 protein expression could be a promising strategy for the inhibition of tumor growth in HPV(+)OSCC and MCV(+)MCC patients.

Original languageEnglish
Article number200264
JournalTumour Virus Research
Volume16
DOIs
StatePublished - Dec 2023

Keywords

  • EZH2 methyltransferase-independent function
  • Enhancer of zeste homolog 2
  • Human papillomavirus
  • Merkel cell carcinoma
  • Merkel cell polyomavirus
  • Oropharyngeal squamous cell carcinoma

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