Abstract
BackgroundThe 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.ResultsOverall, 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.ConclusionThe 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.
Highlights
The methylation status at the human papilloma virus (HPV) genome found in preinvasive and invasive cervical lesions suggests that neoplastic transformation can be suppressed by gene hypermethylation, whereas hypomethylation accompanies or causes cancer progression; 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
Growth inhibition by hydralazine and valproate acid in cervical cancer cells As the initial approach to investigate the possible growthpromoting effect of hydralazine and valproate on HPVpositive cervical cancer cell lines, SiHa, CasKi, and HeLa were cultured in the presence of hydralazine, valproate, and both drugs for 48 h; cell viability was measured at 72 h
E6/E7 gene expression in cervical cancer cell lines To assess whether these epigenome targeting drugs could influence viral oncoprotein expression, E6/E7 transcript expression was assayed by RT-PCR in HPV18-positive CaLo and HeLa cell lines and in HPV16-positive CasKi and SiHa cells
Summary
The methylation status at the human papilloma virus (HPV) genome found in preinvasive and invasive cervical lesions suggests that neoplastic transformation can be suppressed by gene hypermethylation, whereas hypomethylation accompanies or causes cancer progression; 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. A study focused on the methylation of E2, the early gene that contributes to multiple biological processes including viral transcription and viral DNA replication, showed that the ability of E2 protein to bind E2 binding sites (E2BS) in vitro is inhibited by the methylation of these cytosines [9]. These observations may indicate that the methylation state of the viral genome, and that of E2BSs, may vary during the viral life cycle, providing a novel means for modulating E2 function as infection progresses [10]
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