The effects of DNA methylation and histone deacetylase inhibitors on human papillomavirus early gene expression in cervical cancer, an in vitro and clinical study.
The effects of DNA methylation and histone deacetylase inhibitors on human papillomavirus early gene expression in cervical cancer, an in vitro and clinical study.
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DOI：
10.1186/1743-422x-4-18
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发表时间：
2007-02-26
期刊：
影响因子：
4.8
通讯作者：
Dueñas-González A
中科院分区：
文献类型：
--
作者：
de la Cruz-Hernández E;Pérez-Cárdenas E;Contreras-Paredes A;Cantú D;Mohar A;Lizano M;Dueñas-González A
在浸润性和浸润性宫颈病变中发现的人乳头瘤病毒(HPV)基因组的甲基化状态表明，肿瘤转化可以通过基因的高甲基化来抑制，而低甲基化会伴随或导致癌症的进展；因此，旨在重新激活细胞抑制基因表达的表观遗传疗法有可能通过增强HPV相关恶性肿瘤中HPV癌蛋白的表达而起到促进肿瘤的作用。本研究的目的是确定肼和丙戊酸盐对宫颈癌细胞株和接受肼和丙戊酸盐治疗的原发肿瘤患者的HPV癌基因表达的影响。总体而言，肼和丙戊酸盐单独或联合使用对宫颈癌细胞株具有生长抑制作用。细胞株特异性上调E6/E7基因表达，一般与长控制区DNA低甲基化和组蛋白乙酰化有关。然而，在接受肼、丙戊酸盐或两者同时治疗的大多数宫颈癌患者中，E6/E7的表达没有变化或降低。在一些宫颈癌细胞系中，这些药物导致P53转录增加，并由于赖氨酸273和282的乙酰化而增强其稳定性，从而允许更高的Bax蛋白反式激活作用。这项研究的结果表明，肼和丙戊酸盐可以安全地用于治疗HPV相关的恶性肿瘤，如宫颈癌，因为它们不会增加病毒癌蛋白的表达。最重要的是，肼和丙戊酸盐在宫颈癌中的抗肿瘤作用可能至少部分依赖于对P53基因的上调作用，以及丙戊酸诱导的P53蛋白的超乙酰化，保护其免受E6的降解。
The methylation status at the human papilloma virus (HPV) genome found in pre-invasive and invasive cervical lesions suggests that neoplastic transformation can be suppressed by gene hypermethylation, whereas hypomethylation accompanies or causes cancer progression; hence, epigenetic therapy aimed at reactivating cellular suppressor-gene expression has the potential to act as a tumor promoter by enhancing HPV oncoprotein expression in HPV-related malignancies. The objective of this study was to determine the influence of hydralazine and valproate on HPV oncogene expression in cervical cancer cell lines and the primary tumors of patients undergoing treatment with hydralazine and valproate. Overall, hydralazine and valproate either alone or combined exerted a growth inhibitory effect on cervical cancer cell lines. A cell line-specific up-regulating effect was observed on E6/E7 gene expression, which in general correlated with DNA hypomethylation and histone acetylation at the long control region (LCR). Nonetheless, E6/E7 expression was unchanged or decreased in the majority of patients with cervical cancer treated with hydralazine, valproate, or both. In some cervical cancer cell lines, these drugs led to increased transcription of p53, and increased its stabilization due to acetylation at lysines 273 and 282, which allowed a higher bax-protein transactivating effect. The results of this study demonstrate that hydralazine and valproate can be safely administered to HPV-related malignancies such as cervical cancer because they do not increase viral oncoprotein expression. Most importantly, the antitumor effect of hydralazine and valproate in cervical cancer may at least partially depend on an up-regulating effect on p53 gene and on the valproate-induced hyperacetylation of p53 protein, protecting it from degradation by E6.