20 Chapter 1 1.2.3 MOLECULAR HOST-CELL ALTERATIONS IN CERVICAL CARCINOGENESIS The combined disruption of cell cycle control and prevention of apoptosis by viral oncoproteins E6 and E7 in the context of a transforming infection induces genome instability. The gradual accumulation of genetic and epigenetic changes in the host-cell genome, affecting both oncogenes and tumour suppressor genes, along with a persistent hrHPV infection, is considered as a crucial driving force necessary for the progression to cervical cancer. In concordance with this, the number of molecular aberrations increases with the severity of cervical lesions, with the highest numbers being found in cervical cancer 55, 57, 65. Genetic host-cell alterations detected in cervical cancer and CIN2/3 lesions include copy number alterations (CNA) and DNA mutations, and epigenetic changes include altered microRNA (miRNA) expression and DNA methylation 25, 66. 1.2.3.1 DNA METHYLATION DNA methylation is a well-studied epigenetic process that plays an important role in several human processes, such as X-chromosome inactivation, suppression of repetitive element transcription, genomic imprinting and transposition. Epigenetic silencing of hostcell genes by DNA methylation has also proven to be essential for cervical carcinogenesis. DNA methylation entails the covalent binding of a methyl (-CH3) group to the carbon-5 position of a cytosine molecule in CpG dinucleotides and is regulated by the activity of DNA methyltransferases (DNMT) proteins (Figure 1.6). During carcinogenesis, there is a general loss of DNA methylation in the genome, resulting in chromosomal instability, while hypermethylation of promoter regions of tumour suppressor genes with high CpG density, occurs leading to transcriptional repression, altogether contributing to the development of cervical cancer. HPV E6 and E7 oncoproteins interact with several proteins that regulate epigenetic processes, including DNMTs, histone-modifying enzymes and chromatin remodelling complex subunits, influencing the host-cell transcription program. For instance, E6 degrades p53, leading to the upregulation of DNMT1. E7 binds directly to DNMT1. Additionally, E7 indirectly binds to pRB, causing the release of E2F. This results in activation of DNMT1, regulation of promoter activity of DNMT1 and ultimately leads to overexpression of DNMT1. E7 has also been shown to increase the protein levels of DNMT3A and DNMT3B. The interaction between HPV and the cellular DNA methylation machinery can influence the epigenetic regulation of both the viral genome and the host genome. This interplay plays a crucial role in the viral life cycle, but also participates in the maintenance of a persistent infection, cell transformation, and development of invasive
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