Epigenetic Changes in Virus-Associated Neoplasms

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

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.

Keywords

Leukemia Adenocarcinoma Glutathione Recombination Adduct 

Abbreviations

5-caC

5-Carboxylcytosine

5-hmC

5-Hydroxymethylcytosine

5-mC

5-Methylcytosine

AIDS-BL

AIDS-related-BL

APC

Adenomatous polyposis coli

BART

BamHI A rightward transcripts

BCBL

Body cavity-based lymphoma

BL

Burkitt’s lymphoma

CBF1

C promoter-binding factor 1

CGI

CpG island

cHL

Classical Hodgkin’s lymphoma

CIMP

CpG island methylator phenotype

CIN

Cervical intraepithelial neoplasm

CIN

Chromosomal instability

Cp

C promoter

CpG

Cytosine-phosphate-guanine dinucleotide

CRBP

Cellular retinol-binding protein

CTCF

CCCTC-binding factor

DLBCL

Diffuse large B-cell lymphoma

DNMT

DNA methyltransferase

DS

Dyad symmetry

EBER

Epstein–Barr encoded small RNA

eBL

Endemically occurring BL

EBNA

Epstein–Barr nuclear antigen

EBNA-LP

EBNA-leader protein

EBV

Epstein–Barr virus

EZH2

Enhancer of zeste homologue 2

FR

Family of repeats

GC

Gastric carcinoma

GC

Germinal center

GSTP1

Glutathione S-transferase P1

H3K27me3

Histone 3 trimethylated on lysine 27

H3K4me2

Histone 3 dimethylated on lysine 4

H3K4me3

Histone 3 trimethylated on lysine 4

H3K9me3

Histone 3 trimethylated on lysine 9

HBsAg

Hepatitis B surface antigen

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

HDAC

Histone deacetylase

HHV-8

Human herpesvirus-8

HL

Hodgkin’s lymphoma

HP1

Heterochromatin-associated protein 1

HPV

Human papillomavirus

HRS

Hodgkin and Reed–Sternberg cells

HTLV

Human T-lymphotropic virus

IM

Infectious mononucleosis

KDM

Lysine demethylase

KSHV

Kaposi’s sarcoma herpesvirus

LANA

Latency-associated nuclear antigen

LCL

Lymphoblastoid cell line

LCR

Locus control region or long control region

LINE-1

Long interspersed element-1

LMP

Latent membrane protein

LMP2Ap

LMP2A promoter

lncRNA

Long noncoding RNA

MCD

Multicentric Castleman’s disease

MCPyV

Merkel cell polyomavirus

MeCP2

Methylcytosine-binding protein 2

MGMT

O6-methylguanine DNA methyltransferase

miRNA

MicroRNA

NHL

Non-Hodgkin lymphoma

NPC

Nasopharyngeal carcinoma

PAN

Polyadenylated nuclear RNA

PcG

Polycomb group

PEL

Primary effusion lymphoma

PIN

Prostatic intraepithelial neoplasias

pRB

Retinoblastoma protein

PRC

Polycomb repressive complex

PTEN

Phosphatase and tensin homologue

PTLD

Posttransplant lymphoproliferative disorder

Qp

Q promoter

RARβ2

Retinoic acid receptor β2

RARRES

Retinoic acid receptor responder

RASSF1A

RAS association domain family 1 isoform A

sBL

Sporadic BL

SFRP1

Secreted frizzled-related protein 1

siRNA

Short interfering RNA

snoRNA

Small nucleolar RNA

SOCS

Suppressor of cytokine signaling

TAg

T antigen

TR

Terminal repeat

TrxG

Trithorax group

Wp

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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