EPIGENETIC ALTERATIONS INDUCED BY GYNECOLOGY ONCOVIRUSES FROM VIRAL PERSISTENCE TO CARCINOGENESIS

Abstract

Gynecologic oncoviruses that are important in the genesis of malignancies of the female reproductive tract include Human Papillomavirus (HPV), Epstein - Barr virus (EBV), and Human Herpesviruses (HHV). These DNA viruses become persistent or latent infections by regulating host DNA epigenetics to avoid recognition by the immune system and induce oncogenesis. Oncoproteins of viruses (e.g., HPV E6/E7, EBV LMP1/EBNA1) bind DNA methyltransferases, histone modifiers, and non-coding RNAs which results in hypermethylated tumor-suppressor genes (p53, Rb, PTEN) and activation of oncogenic pathways (PI3K/AKT and MAPK). Gene silencing by DNA methylation of viral and cellular promoters keeps the virus in latency, whereas immune evasion (H3K9me3, H3K27me3) and antiforapoptotic (miR-BARTs, miR-203) viral microRNAs keep the viruses hidden. The accrued epigenetic reprogramming of host chromatin results in instability of the genome and generation of a pro-oncogenic microenvironment which propagates malignant transformation. These epigenetic changes caused by the virus are clinically promising diagnostic biomarkers (e.g., CADM1, MAL, miR-124) and potential therapeutic targets, with DNMT and HDAC inhibitors labeling to restore normal expression of these genes. HPV vaccination and antiviral therapy are further preventive measures that induce viral epigenetics to decrease the persistence of infections and cancer. This complex interaction of viral persistence by host epigenetic control offers novel information on precision-based gynecologic oncology, with a potential of using reversible epigenetic processes to prevent or treat cancerous lesions associated with the virus.