Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus
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) thr...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Tumour Virus Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666679023000113 |
| _version_ | 1797385002299686912 |
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| author | Michelle Khattri Yutaka Amako Julia R. Gibbs Joseph L. Collura Reety Arora Alexis Harold Meng Yen Li Paul W. Harms Elena Ezhkova Masahiro Shuda |
| author_facet | Michelle Khattri Yutaka Amako Julia R. Gibbs Joseph L. Collura Reety Arora Alexis Harold Meng Yen Li Paul W. Harms Elena Ezhkova Masahiro Shuda |
| author_sort | Michelle Khattri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T21:47:50Z |
| format | Article |
| id | doaj.art-21243291011448e1985c928eb3726581 |
| institution | Directory Open Access Journal |
| issn | 2666-6790 |
| language | English |
| last_indexed | 2024-03-08T21:47:50Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Tumour Virus Research |
| spelling | doaj.art-21243291011448e1985c928eb37265812023-12-20T07:39:14ZengElsevierTumour Virus Research2666-67902023-12-0116200264Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirusMichelle Khattri0Yutaka Amako1Julia R. Gibbs2Joseph L. Collura3Reety Arora4Alexis Harold5Meng Yen Li6Paul W. Harms7Elena Ezhkova8Masahiro Shuda9Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USACancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USACancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USACancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USANational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, IndiaCancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USADevelopmental and Regenerative Biology, Mt. Sinai School of Medicine, New York, NY, USA; Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, 10029, USADepartments of Pathology and Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USADevelopmental and Regenerative Biology, Mt. Sinai School of Medicine, New York, NY, USA; Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, 10029, USACancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author. University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.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.http://www.sciencedirect.com/science/article/pii/S2666679023000113Merkel cell polyomavirusMerkel cell carcinomaHuman papillomavirusOropharyngeal squamous cell carcinomaEnhancer of zeste homolog 2EZH2 methyltransferase-independent function |
| spellingShingle | Michelle Khattri Yutaka Amako Julia R. Gibbs Joseph L. Collura Reety Arora Alexis Harold Meng Yen Li Paul W. Harms Elena Ezhkova Masahiro Shuda Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus Tumour Virus Research Merkel cell polyomavirus Merkel cell carcinoma Human papillomavirus Oropharyngeal squamous cell carcinoma Enhancer of zeste homolog 2 EZH2 methyltransferase-independent function |
| title | Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus |
| title_full | Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus |
| title_fullStr | Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus |
| title_full_unstemmed | Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus |
| title_short | Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus |
| title_sort | methyltransferase independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus |
| topic | Merkel cell polyomavirus Merkel cell carcinoma Human papillomavirus Oropharyngeal squamous cell carcinoma Enhancer of zeste homolog 2 EZH2 methyltransferase-independent function |
| url | http://www.sciencedirect.com/science/article/pii/S2666679023000113 |
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