Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer (original) (raw)
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The Involvement of Epigenetic Mechanisms in HPV‐Induced Cervical Cancer
Human Papillomavirus - Research in a Global Perspective, 2016
High-risk human papillomavirus (HPV) genotypes infection associates with cervical dysplasia and carcinogenesis. hr-HPV transforming potential is based on E6 and E7 viral oncoproteins actions on cellular proteins. A persistent infection with hr-HPV leads to progression from precursor lesions to invasive cervical cancer inducing changes in host genome and epigenome. Pathogenesis and development of cancer associated with both genetic and epigenetic defects alter transcriptional program. An important role for malignant transformation in HPV-induced cervical cancer is played by epigenetic changes that occur in both viral and host genome. Furthermore, there are observations demonstrating that oncogenic viruses, once they integrated into host genome, become susceptible to epigenetic alterations made by host machinery. Epigenetic regulation of viral gene expression is an important factor in HPV-associated disease. Gene expression control is complex and involves epigenetic changes: DNA methylation, histone modification, and non-coding RNAs activity. Persistent infection with hr-HPV can cause viral DNA integration into host genome attracting defense mechanisms such as methylation machinery. In this chapter, we aim to review HPV infection role in chromatin modification/ remodeling and the impact of HPV infection on non-coding RNAs in cervix oncogenesis. The reversible nature of epigenetic alterations provides new opportunities in the development of therapeutic agents targeting epigenetic modification in oncogenesis.
Carcinogenesis, 2012
The contribution of early virus-induced epigenetic changes to human papillomavirus (HPV)-associated carcinogenesis is poorly understood. Using genome-wide methylation array profiling and a cell-based model, which supports replication of HPV episomes, we found that transfection of primary human foreskin keratinocytes with episomal forms of high-risk HPV types was followed by upregulation of the DNA methyltransferases, DNMT1 and DNMT3B, and changes in the methylation status of cellular genes many of which are reported to be differentially methylated in cervical neoplasia. HPV16-and HPV18-associated changes were not randomly distributed across the genome, but clustered at specific chromosomal locations which mapped on to known HPV integration sites and to chromosomal regions lost and gained in highgrade cervical neoplasia. Methylation changes were directed in part by the same cis-acting factors that appear to direct methylation changes in cancer, the presence of a bivalent chromatin mark in human embryonic stem cells and promoter CpG content; these associations explain much of the ontological profile of genes found to have increased methylation following HPV16 transfection. We were also able to show, using sequential samples from a cohort of young women with incident HPV16 infections, that the detection in cervical samples of methylated forms of the tumour suppressor gene, RARB, often parallels the natural history of cervical HPV infection. Our findings suggest that further investigation of the distribution and determinants of early virus-induced epigenetic reprogramming will provide important insights into the pathogenesis of virus-associated malignancy.
The role of HPV‑induced epigenetic changes in cervical carcinogenesis (Review)
Biomedical Reports, 2021
Cervical cancer is associated with infection by certain types of human papillomaviruses (HPVs), and this affects women worldwide. Despite the improvements in prevention and cure of HPV-induced cervical cancer, it remains the second most common type of cancer in women in the least developed regions of the world. Epigenetic modifications are stable long-term changes that occur in the DNA, and are part of a natural evolutionary process of necessary adaptations to the environment. They do not result in changes in the DNA sequence, but do affect gene expression and genomic stability. Epigenetic changes are important in several biological processes. The effects of the environment on gene expression can contribute to the development of numerous diseases. Epigenetic modifications may serve a critical role in cancer cells, by silencing tumor suppressor genes, activating oncogenes, and exacerbating defects in DNA repair mechanisms. Although cervical cancer is directly related to a persistent high-risk HPV infection, several epigenetic changes have been identified in both the viral DNA and the genome of the infected cells: DNA methylation, histone modification and gene silencing by non-coding RNAs, which initiate and sustain epigenetic changes. In the present review, recent advances in the role of epigenetic changes in cervical cancer are summarized.
Role of DNA methylation in HPV associated lesions
Papillomavirus Research, 2019
Papillomavirus replication is tightly linked to squamous epithelial differentiation which in turn is governed to a large extent by epigenetic remodeling of genomes within the differentiating squamous epithelial cells. Over the past years it became evident that epigenetic and in particular differential methylation events substantially contribute to the regulation of the papillomavirus life cycle. Moreover, there is now good evidence that the initial trigger for HPV-mediated transformation of squamous epithelial cells is mediated by methylation of distinct CpG dinucleotides within E2-binding sites of the papillomavirus upstream regulatory region (URR). These findings have important implications for novel diagnostic markers but also for novel and indeed targeted therapy strategies for HPV linked neoplastic lesions.
DNA Methylation Changes in Human Papillomavirus-Driven Head and Neck Cancers
Cells
Disruption of DNA methylation patterns is one of the hallmarks of cancer. Similar to other cancer types, human papillomavirus (HPV)-driven head and neck cancer (HNC) also reveals alterations in its methylation profile. The intrinsic ability of HPV oncoproteins E6 and E7 to interfere with DNA methyltransferase activity contributes to these methylation changes. There are many genes that have been reported to be differentially methylated in HPV-driven HNC. Some of these genes are involved in major cellular pathways, indicating that DNA methylation, at least in certain instances, may contribute to the development and progression of HPV-driven HNC. Furthermore, the HPV genome itself becomes a target of the cellular DNA methylation machinery. Some of these methylation changes appearing in the viral long control region (LCR) may contribute to uncontrolled oncoprotein expression, leading to carcinogenesis. Consistent with these observations, demethylation therapy appears to have significant...
Impact of viral and host DNA methylations on HPV16-related cervical cancer pathogenesis
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2017
Epigenetic alterations within human papillomavirus (HPV) and host cellular genomes are known to occur during cervical carcinogenesis. Our objective was to analyse the influence of (1) methylation within two immunostimulatory CpG motifs within HPV16 E6 and E7 genes around the viral late promoter and their correlation, if any, with expression deregulation of host receptor (TLR9) and DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) and (2) global DNA methylation levels within CpGs of the repetitive Alu sequences, on cervical cancer (CaCx) pathogenesis. Significantly higher proportions of CaCx samples portrayed methylation in immunostimulatory CpG motifs, compared to HPV16-positive non-malignant samples, with cases harbouring episomal HPV16 showing decreased methylation compared to those with viral integration. A significant linear trend of TLR9 upregulation was recorded in the order of HPV-negative controls < HPV16-positive non-malignant samples < HPV16-positive CaCx cases. TLR9...
Epigenetics of cervical cancer. An overview and therapeutic perspectives
Molecular cancer, 2005
Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissue...
Journal of …, 2004
DNA methylation contributes to the chromatin conformation that represses transcription of human papillomavirus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In an effort to clarify the role of this phenomenon in the regulation and carcinogenicity of HPV-16, 115 clinical samples were studied to establish the methylation patterns of the 19 CpG dinucleotides within the long control region and part of the L1 gene by bisulfite modification, PCR amplification, DNA cloning, and sequencing. We observed major heterogeneities between clones from different samples as well as between clones from individual samples. The methylation frequency of CpGs was measured at 14.5%. In addition, 0.21 and 0.23%, respectively, of the CpA and CpT sites, indicators of de novo methylation, were methylated. Methylation frequencies exceeded 30% in the CpGs overlapping with the L1 gene and were about 10% for most other positions. A CpG site located in the linker between two nucleosomes positioned over the enhancer and promoter of HPV-16 had minimal methylation. This region forms part of the HPV replication origin and is close to binding sites of master-regulators of transcription during epithelial differentiation. Methylation of most sites was highest in carcinomas, possibly due to tandem repetition and chromosomal integration of HPV-16 DNA. Methylation was lowest in dysplasia, likely reflecting the transcriptional activity in these infections. Our data document the efficient targeting of HPV genomes by the epithelial methylation machinery, possibly as a cellular defense mechanism, and suggest involvement of methylation in HPV oncogene expression and the early-late switch.
The Role of Epigenetics in Cervical Cancer
Gynaecological Malignancies - Updates and Advances, 2020
Cervical cancer is the fourth most common type of cancer among women worldwide resulting in 528,475 new cases and 268,224 deaths. The principal etiological factor of cervical cancer is the persistent infection with high-risk types of human papillomaviruses (HPV), however is not sufficient, other factors like age, smoking, oral contraceptives, and genetic background are implicated in the development of this neoplasia. Although the understanding of cervical carcinogenesis has been increasing in recent decades, the epigenetic modifications (DNA methylation, histone modification, miRNAs and long non-coding RNAs) and its contribution to the development of cervical cancer remain largely unknown. In the next chapter, we will recapitulate the described findings on the alteration of epigenetic factors that, together with the persistent infection of HPV, could contribute to the malignant and invasive phenotype in cervical cancer.
The human papillomavirus-18 genome is efficiently targeted by cellular DNA methylation
Virology, 2004
Human papillomaviruses (HPVs) infect epithelia, including the simple and the squamous epithelia of the cervix, where they can cause cancer and precursor lesions. The molecular events leading from asymptomatic HPV infections to neoplasia are poorly understood. There is evidence that progression is modulated by transcriptional mechanisms that control HPV gene expression. Here, we report the frequent methylation of HPV-18 genomes in cell culture and in situ. DNA methylation is generally known to lead to transcriptional repression due to chromatin changes. We investigated two cell lines derived from cervical cancers, namely, C4-1, which contains one HPV-18 genome, and different clones of HeLa, with 50 HPV-18 genomes. By restriction cleavage, we detected strong methylation of the L1 gene and absence of methylation of parts of the long control region (LCR). A 3-kb segment of the HPV-18 genomes downstream of the oncogenes was deleted in both cell lines. Bisulfite sequencing showed that in C4-1 cells and two HeLa clones, 18 of the 19 CpG residues in the 1.2-kb terminal part of the L1 gene were methylated, whereas a third HeLa clone had only eight methylated CpG groups, indicating changes of the methylation pattern after the establishment of the HeLa cell line. In the same four clones, none of the 12 CpG residues that overlapped with the enhancer and promoter was methylated. In six HPV-18 containing cancers and five smears from asymptomatic patients, most of the CpG residues in the L1 gene were methylated. There was complete or partial methylation, respectively, of the HPV enhancer in three of the cancers, and lack of methylation in the remaining eight samples. The promoter sequences were methylated in three of the six cancers and four of the six smears, and unmethylated elsewhere. Our data show that epithelial cells efficiently target HPV-18 genomes for DNA methylation, which may affect late and early gene transcription.