Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus.
Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus.
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DOI：
10.1016/j.tvr.2023.200264
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发表时间：
2023-12
影响因子：
4.3
通讯作者：
Shuda M
中科院分区：
文献类型：
--
作者：
Khattri M;Amako Y;Gibbs JR;Collura JL;Arora R;Harold A;Li MY;Harms PW;Ezhkova E;Shuda M
默克尔细胞多瘤病毒（MCV）和高危型人乳头瘤病毒（HPV）是分别引起默克尔细胞癌（MCC）和口咽鳞状细胞癌（OSCC）的人类肿瘤病毒。HPV E7和MCV大T（LT）癌蛋白通过保守的LxCxE基序靶向视网膜母细胞瘤肿瘤抑制蛋白（pRb）。我们确定增强子zeste同源物2（EZH 2）作为一个共同的宿主癌蛋白激活的两种病毒癌蛋白通过pRb结合基序。EZH 2是polycomb 2（PRC 2）复合物的催化亚基，其使组蛋白H3在赖氨酸27处三甲基化（H3 K27 me 3）。在MCC组织中，EZH 2高表达，与MCV状态无关。功能丧失研究表明，EZH 2 mRNA表达需要病毒HPV E6/E7和T抗原表达，EZH 2对HPV（+）OSCC和MCV（+）MCC细胞生长至关重要。此外，EZH 2蛋白降解剂在HPV（+）OSCC和MCV（+）MCC细胞中有效且快速地降低细胞活力，而EZH 2组蛋白甲基转移酶抑制剂在相同的处理期内不影响细胞增殖或活力。这些结果表明，EZH 2的甲基转移酶非依赖性功能有助于两种病毒癌蛋白下游的肿瘤发生，并且直接靶向EZH 2蛋白表达可能是抑制HPV（+）OSCC和MCV（+）MCC患者肿瘤生长的有希望的策略。
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.
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DOI：
10.1186/s40463-016-0168-9
发表时间：
2016-10-28
期刊：
Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale
影响因子：
--
作者：
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影响因子：
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发表时间：
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期刊：
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影响因子：
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影响因子：
0.8
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Acikalin, Arbil;Bagir, Emine;Paydas, Semra
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DOI：
10.1097/jto.0b013e318298762f
发表时间：
2013-08
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
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作者：
Hubaux R;Thu KL;Coe BP;MacAulay C;Lam S;Lam WL
通讯作者：
Lam WL