Epigenetic Changes in Virus-Associated Neoplasms

  • Hans Helmut Niller
  • Ferenc Banati
  • Eva Ay
  • Janos Minarovits


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.


Merkel Cell Carcinoma Cellular Promoter Merkel Cell Polyomavirus KSHV Episome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.











Adenomatous polyposis coli


BamHI A rightward transcripts


Body cavity-based lymphoma


Burkitt’s lymphoma


C promoter-binding factor 1


CpG island


Classical Hodgkin’s lymphoma


CpG island methylator phenotype


Cervical intraepithelial neoplasm


Chromosomal instability


C promoter


Cytosine-phosphate-guanine dinucleotide


Cellular retinol-binding protein


CCCTC-binding factor


Diffuse large B-cell lymphoma


DNA methyltransferase


Dyad symmetry


Epstein–Barr encoded small RNA


Endemically occurring BL


Epstein–Barr nuclear antigen


EBNA-leader protein


Epstein–Barr virus


Enhancer of zeste homologue 2


Family of repeats


Gastric carcinoma


Germinal center


Glutathione S-transferase P1


Histone 3 trimethylated on lysine 27


Histone 3 dimethylated on lysine 4


Histone 3 trimethylated on lysine 4


Histone 3 trimethylated on lysine 9


Hepatitis B surface antigen


Hepatitis B virus


Hepatocellular carcinoma


Hepatitis C virus


Histone deacetylase


Human herpesvirus-8


Hodgkin’s lymphoma


Heterochromatin-associated protein 1


Human papillomavirus


Hodgkin and Reed–Sternberg cells


Human T-lymphotropic virus


Infectious mononucleosis


Lysine demethylase


Kaposi’s sarcoma herpesvirus


Latency-associated nuclear antigen


Lymphoblastoid cell line


Locus control region or long control region


Long interspersed element-1


Latent membrane protein


LMP2A promoter


Long noncoding RNA


Multicentric Castleman’s disease


Merkel cell polyomavirus


Methylcytosine-binding protein 2


O6-methylguanine DNA methyltransferase




Non-Hodgkin lymphoma


Nasopharyngeal carcinoma


Polyadenylated nuclear RNA


Polycomb group


Primary effusion lymphoma


Prostatic intraepithelial neoplasias


Retinoblastoma protein


Polycomb repressive complex


Phosphatase and tensin homologue


Posttransplant lymphoproliferative disorder


Q promoter


Retinoic acid receptor β2


Retinoic acid receptor responder


RAS association domain family 1 isoform A


Sporadic BL


Secreted frizzled-related protein 1


Short interfering RNA


Small nucleolar RNA


Suppressor of cytokine signaling


T antigen


Terminal repeat


Trithorax group


W promoter


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Hans Helmut Niller
    • 1
  • Ferenc Banati
    • 2
  • Eva Ay
    • 2
  • Janos Minarovits
    • 2
  1. 1.Institute for Medical Microbiology and Hygiene at the University of RegensburgRegensburgGermany
  2. 2.Microbiological Research GroupNational Center for EpidemiologyBudapestHungary

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