Epigenetic changes in virus-associated neoplasms

Abstract

The viruses associated with malignant tumors in humans include DNA viruses (Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis B virus (HBV), human papillomavirus, Merkel cell polyomavirus) and a retrovirus replicating through a DNA intermediate (human T-lymphotropic virus, HTLV). Although Merkel cell polyomavirus remains yet to be studied, the expression of human tumor virus genomes is certainly affected by the cellular epigenetic machinery. A remarkable exception is hepatitis C virus (HCV), which causes a persistent infection: as far as we know, the RNA genome of HCV is exempt from the epigenetic control of the host cell. All of the human tumor viruses code for oncoproteins capable to modulate the epigenome of the host cell. The latent membrane protein 1 (LMP1) of EBV upregulates all three cellular DNA methyltransferases (DNMTs) as well as the PcG group protein Bmi-1, resulting in silencing of cellular promoters. LMP2, also encoded by EBV, may induce DNMT1, similarly to LMP1. LANA, a latency-associated nuclear antigen of KSHV recruits DNMTs and histone deacetylases to the chromatin of selected cellular promoters. The HTLV-encoded Tax displaces transcription factors from the promoter of Shp1, a gene coding for the Src homology containing protein tyrosine phosphatase, followed by promoter hypermethylation. The viral oncoprotein HB-X (also called pX), a pleiotropic regulator expressed in hepatocarcinoma cells carrying HBV genomes, inhibits the expression of selected tumor suppressor genes by upregulating DNMT1 and DNMT3A. The HCV core protein is capable to activate DNMT1 and DNMT3B, to silence a distinct set of promoters in HCV-associated liver cancer. Gene suppression is achieved by the E6 oncoprotein in HPV-transformed cells by blocking the activities of coactivator protein arginine and protein lysine methyltransferases. The E7 oncoprotein of the highly oncogenic human papillomavirus, HPV-16, may induce hypermethylation of selected cellular promoters both directly, by binding to DNMT1 and stimulating its activity, and indirectly, by releasing the so-called activating E2F transcription factors that are complexed with members of the retinoblastoma pocket protein family. E2F activates DNMT1 transcription. A similar, indirect mechanism may operate in Merkel cell carcinomas expressing the tumor antigen (TAg) of Merkel cell polyomavirus, resulting in silencing of ATOH1, a master regulator gene. Activating DNA and chromatin modifications regularly also occur in virus-associated neoplasms. The nuclear antigen EBNA1 of EBV may induce local, whereas HB-X of HBV may elicit global DNA hypomethylation. HB-X acts by downregulating DNMT3B involved in the methylation of satellite 2 repeat sequences. The EBV nuclear antigen EBNA2, a transactivator protein, interacts with histone acetyltransferases to establish an activating chromatin conformation at cellular and viral promoters. The coactivator EBNA-LP (EBNA5) promotes this process by the displacement of the histone deacetylase HDAC4 from EBNA2-activated promoters. Whereas LMP1 silences certain promoters in EBV-infected cells, in parallel it activates others. LMP1 induces KDM6B, a histone H3K27me3 demethylase which removes the trimethyl mark from lysine 27 of histone H3 and thereby dissociates PRC1 (polycomb repressive complexes) from their binding sites, resulting in target gene activation. In KSHV-infected cells, LANA also can act both as a silencer and as an activator of promoter activity in a context-dependent manner. MeCP2, a methylcytosine-binding protein, may facilitate both the repressor and the transactivating function of LANA, depending on the promoter analyzed. In addition, LANA induces changes in the positioning of chromosomal domains in interphase nuclei. E7 also has a dual function, involved not only in gene silencing but also in gene activation. In human keratinocytes, HPV-16 E7 increased histone H3 acetylation at the E2F1 and CDC25A promoters. In addition, similarly to LMP1, E7 modulates histone methylation patterns as well: it induces the lysine demethylases KDM6A and KDM6B that target histone H3K27me3 and disrupt polycomb repressor complexes. Elucidation of the complex virus-induced pathoepigenetic alterations may pinpoint new targets for the therapy of virus-associated neoplasms.