Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes
Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes
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DOI：
10.1128/jvi.00160-11
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发表时间：
2011-11-01
影响因子：
5.4
通讯作者：
Patel, Daksha
中科院分区：
文献类型：
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作者：
Hyland, Paula L.;McDade, Simon S.;Patel, Daksha
在人乳头瘤病毒（HPV）相关的致癌过程中，病毒和宿主细胞基因组都发生了许多表观遗传改变，对这些改变的研究，包括染色质蛋白和组蛋白修饰的变化，有可能导致治疗性表观遗传逆转。我们在这里报告，转化的HPV 16 E6/E7表达原代人包皮角质形成细胞（HFKs）（E6/E7细胞）表现出增加的PRC 2甲基转移酶EZH 2在mRNA和蛋白质水平的表达，但没有表现出预期的增加三甲基化H3 K27（H3 K27 me 3）相比，正常角质形成细胞。相反，这些细胞显示出体外整体H3 K27 me 3水平的降低，以及KDM 6A脱甲基酶的上调。我们还首次表明，用HPV 16 E6和E7癌基因转化也导致由活性Akt介导的磷酸化EZH 2丝氨酸21（P-EZH 2-Ser 21）的增加，以及这些细胞中PRC 1蛋白BMI 1的下调。高级别鳞状宫颈上皮内病变也表现出H3 K27 me 3的丢失，EZH 2的表达增加。与H3 K27 me 3的缺失相关，E6/E7细胞表现出特异性EZH 2-、KMD 6A-和BMI 1-靶向HOX基因的去抑制。这些结果表明，观察到的H3 K27 me 3的减少可能是由于特定多梳蛋白的活性/水平降低和脱甲基酶增加的组合。导致HPV 16 E6/E7感染细胞中全局H3 K27 me 3丢失和转录重编程的多种染色质蛋白的失调可以提供与HPV 16相关癌症的风险和/或进展相关的表观遗传特征，以及未来表观遗传逆转的可能性。
A number of epigenetic alterations occur in both the virus and host cellular genomes during human papillomavirus (HPV)-associated carcinogenesis, and investigations of such alterations, including changes in chromatin proteins and histone modifications, have the potential to lead to therapeutic epigenetic reversion. We report here that transformed HPV16 E6/E7-expressing primary human foreskin keratinocytes (HFKs) (E6/E7 cells) demonstrate increased expression of the PRC2 methyltransferase EZH2 at both the mRNA and protein levels but do not exhibit the expected increase in trimethylated H3K27 (H3K27me3) compared to normal keratinocytes. In contrast, these cells show a reduction in global H3K27me3 levels in vitro, as well as upregulation of the KDM6A demethylase. We further show for the first time that transformation with the HPV16 E6 and E7 oncogenes also results in an increase in phosphorylated EZH2 serine 21 (P-EZH2-Ser21), mediated by active Akt, and in a downregulation of the PRC1 protein BMI1 in these cells. High-grade squamous cervical intraepithelial lesions also showed a loss of H3K27me3 in the presence of increased expression of EZH2. Correlating with the loss of H3K27me3, E6/E7 cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. These results suggest that the observed reduction in H3K27me3 may be due to a combination of reduced activities/levels of specific polycomb proteins and increases in demethylases. The dysregulation of multiple chromatin proteins resulting in the loss of global H3K27me3 and the transcriptional reprogramming in HPV16 E6/E7-infected cells could provide an epigenetic signature associated with risk and/or progression of HPV16-associated cancers, as well as the potential for epigenetic reversion in the future.