biomolecules
Review
The Role of Epstein-Barr Virus in Modulating Key Tumor
Suppressor Genes in Associated Malignancies: Epigenetics,
Transcriptional, and Post-Translational Modifications
Adelaide Ohui Fierti , Michael Bright Yakass , Ernest Adjei Okertchiri, Samuel Mawuli Adadey
and Osbourne Quaye *
West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry,
Cell and Molecular Biology, University of Ghana, Accra P.O. Box LG 54, Ghana; aofierti@st.ug.edu.gh (A.O.F.);
mbyakass@st.ug.edu.gh (M.B.Y.); eaokertchiri@st.ug.edu.gh (E.A.O.); smadadey@st.ug.edu.gh (S.M.A.)
* Correspondence: oquaye@ug.edu.gh
Abstract: Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s
adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates
the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma,
nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral
proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-
Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of
some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation



 of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor


suppressor proteins. This review summarizes the mechanisms by which EBV modulates different
Citation: Fierti, A.O.; Yakass, M.B.;
Okertchiri, E.A.; Adadey, S.M.; tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene
Quaye, O. The Role of Epstein-Barr products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via
Virus in Modulating Key Tumor hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor
Suppressor Genes in Associated suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor
Malignancies: Epigenetics, proteins to inactivate them. All these processes result in downregulation and impaired function of
Transcriptional, and Post- tumor suppressors, ultimately promoting malignances.
Translational Modifications.
Biomolecules 2022, 12, 127. https:// Keywords: Epstein-Barr Virus; cancer; tumor suppressor genes; epigenetic; post-translational
doi.org/10.3390/biom12010127 modifications; EBV nuclear antigens; latent membrane proteins
Academic Editor: Marshall
Williams
Received: 3 December 2021 1. Introduction
Accepted: 5 January 2022
Published: 13 January 2022 Epstein-Barr Virus (EBV) is a human herpesvirus composed of a linear double-stranded
DNA of approximately 172 kbp. EBV is ubiquitous and is carried by approximately 90% of
Publisher’s Note: MDPI stays neutral the world’s adult population [1,2]. The virus exhibits two life cycles, namely, the latent and
with regard to jurisdictional claims in lytic cycles. In the latent life cycle, the viral genome exists as an episome in the nucleus
published maps and institutional affil- of the host cell and replicates simultaneously as the host genome replicates. In the lytic
iations. replication cycle, the virus encodes for its DNA replication complex to replicate its genome
in higher folds, causing the cell to lyse and release the newly formed viruses [3–6].
EBV has been described to have tropism mainly for nasopharyngeal epithelial cells and
Copyright: © 2022 by the authors. B cells [7–9], but infection of other cell types, such as natural killer cells, smooth muscle cells,
Licensee MDPI, Basel, Switzerland. and T cells, have also been reported [8]. While B cells have been suggested to be a reservoir
This article is an open access article for latent EBV, epithelial cells are a site for lytic replication [8]. The virus has been found to
distributed under the terms and be associated with several malignancies, including gastric carcinoma, Hodgkin’s lymphoma,
conditions of the Creative Commons leiomyosarcomas, lymphoepithelioma-like carcinoma, and nasopharyngeal carcinoma
Attribution (CC BY) license (https:// (NPC), with NPC being the most associated [10–12]. A comprehensive survey in 2014
creativecommons.org/licenses/by/ reported an estimated 143,000 deaths globally as a result of EBV-attributed malignancies in
4.0/). 2010, representing 1.8% of all cancer deaths [13]. Out of the estimated deaths recorded due
Biomolecules 2022, 12, 127. https://doi.org/10.3390/biom12010127 https://www.mdpi.com/journal/biomolecules
Biomolecules 2022, 12, 127 2 of 17
to the presence of EBV-related malignancies, gastric cancer and nasopharyngeal carcinoma
accounted for 92%, and 47% occurred in East Asia consisting of China, Taiwan, and the
Democratic People’s Republic of Korea [13].
Several mechanisms and pathways have been proposed as to how EBV facilitates the
pathogenesis and progression of malignancies, the majority of which have been linked
to viral proteins that are expressed upon infection including latent membrane proteins
(LMPs) and Epstein-Barr virus nuclear antigens (EBNAs) [14]. EBNA-1, one of the first
EBV proteins that are expressed upon initial infection and essential for viral DNA repli-
cation in the host cell, binds to a specific sequence at the origin of replication of the viral
genome to regulate expression of other EBNAs, latent membrane proteins, and other latency
genes to facilitate latent infection [15,16]. EBNA-1 directly inhibits phosphorylation of
IKK-alpha/beta which results in the inhibition of the canonical NF-κB pathway [16], a
signaling pathway that is critical in the regulation of cell differentiation, cell growth, and
apoptosis and, hence, carcinogenesis [17]. EBNA-1 has also been shown to indirectly modu-
late the function of p53 to promote cell survival [15]. Another important EBV latency gene
product is LMP1; this protein modulates the replication/expression of the EBV genome
as well as the host genome [18]. LMP1 is a 63 kDa protein that contains an N-terminal
cytoplasmic domain that orients the protein to the plasma membrane, hydrophobic trans-
membrane loops that allow for oligomerization, and a C-terminal cytoplasmic domain that
is involved in signaling [19]. C-terminal activation regions 1 and 2 (CTAR 1 and CTAR 2)
are two different functional domains that are distinguished by the difference in their ability
to activate the nuclear factor-κB (NF-κB) signaling pathway [20]. LMP1 is involved in
the activation of several other pathways, including the signal transducer and activator
of transcription (STAT) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, and
the activating protein 1 (AP-1) pathway, to enhance cell proliferation, cell survival, and to
suppress apoptosis [18].
This review aimed to summarize the mechanisms by which EBV modulates different
tumor suppressors at the molecular and cellular levels in various cancers.
2. EBV Associated Malignancies
2.1. Burkitt’s Lymphoma
Burkitt’s lymphoma (BL) is a non-Hodgkin’s lymphoma that aggressively affects
B cells, mostly in children [21]. It was first identified by Dennis Burkitt in 1958 in Uganda,
and cases are still being recorded in Africa, the United States of America, and Europe. The
incidence of BL is more prevalent in Eastern Africa and contributed to approximately 20%
of childhood cancers in Uganda within the years of 1993–1997 [22]. A recent survey in
Africa, in 2018, indicated that BL contributes to approximately 50% of all pediatric cancers
(with a total incidence of 3900) and is predominantly reported among children of 14 years
of age and below [23].
The World Health Organization (WHO) has classified Burkitt’s Lymphoma into three
different categories based on pathological features and geographical locations: endemic
Burkitt’s lymphoma, sporadic Burkitt’s lymphoma, and immunodeficiency-associated
Burkitt’s lymphoma. Endemic Burkitt’s lymphoma mainly affects African children within
2–14 years of age and occurs in males twice as often as it occurs in females [24,25]. EBV
infection and malaria are both associated with the endemic subtype of BL [25]. Sporadic
Burkitt’s lymphoma affects the lymph nodes in individuals of all ages and is prevalent
in the United States of America and Europe with less than 20% of the cases associated
with EBV [25–27]. Immunodeficiency-associated Burkitt’s Lymphoma is predominant in
HIV patients with CD4 counts usually above 200 cells/µL and may be present in other
forms of immunodeficiencies such as patients who have undergone immunosuppressive
therapy due to the fact of organ transplant [26]. The immunodeficiency-associated Burkitt’s
lymphoma usually affects lymph nodes, bone marrow, and the central nervous system [24].
Biomolecules 2022, 12, 127 3 of 17
2.2. Nasopharyngeal Carcinoma
Nasopharyngeal carcinoma (NPC) is a tumor of the nasopharynx, and it arises from the
epithelial squamous cell [28]. The association of EBV with nasopharyngeal carcinoma was
first established in 1966, where NPC patients were found to express antibodies against EBV
antigens [29]. NPCs have been reported to be endemic to southern China and Southeast
Asia, accounting for approximately 80% of the 65,000 annual cases recorded globally [10,30].
Whereas the lytic phase of EBV predominates in normal epithelial cells, and the latent
phase of EBV predominates in epithelial cells in nasopharyngeal carcinoma [10].
Four stages of NPC have been described that include stages I–IV [31]. The Union for
International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC)
developed the TNM (tumor, node, and metastasis) staging system to describe the levels of
severity within an NPC stage [32]. Stage I describes a small tumor which has neither spread
to a lymph node nor has distant metastasis. Stage II describes a tumor in the nasopharynx
that has spread to the lymph node in the neck with the presence of EBV in lymph, but the
spread is not to the extent of distant metastasis. Stage III describes a large tumor invasive
or noninvasive which may spread to the lymph nodes on either side of the neck with no
metastasis. Stage IV carcinoma presents an extremely large invasive tumor with lymph
involvement with or without extensive metastasis. The NPC staging system is relevant for
understanding how to therapeutically approach NPC cases [31].
Several histological classifications of NPC have been proposed over the years, but
the most widely used is the classification by the WHO, which according to many sources,
has limitations that affect prognosis and treatment [33,34]. WHO classified NPC into
three types: squamous cell carcinoma (type I), non-keratinizing carcinoma (type II), and
undifferentiated carcinoma (type III) [35]. Whereas types II and III are mostly associated
with higher loads of EBV, type I is not.
Many risk factors have been attributed to NPC pathogenesis, which may be envi-
ronmental, pathogen-mediated, lifestyle, and genetic. A case-referent study conducted in
Hong Kong, China, revealed that certain occupations in the craft industry or occupations
that expose people to chemical and welding fumes and cotton dust, may put one at risk
of NPC [36]. Another study in NPC endemic areas of southern China, conducted among
1049 NPC cases and 785 NPC-free controls who were positive for EBV, also disclosed family
history as a risk factor, especially first-to-third-degree relatives, which may account for the
genetic factors [37]. The study also reported the risk of certain lifestyle factors that may
include high consumption of salted fish, more than 10 years of exposure to domestic wood-
cooking fires, and occupational solvents such as acetone, xylene, and formaldehyde. The
authors, however, estimated that the family history and environmental factors accounted
for a smaller percentage (2.7%) of NPC pathogenesis within high-risk populations [37]. It is
widely known that the major risk factor in the development of NPC is EBV infection [38–40];
upon latent infection, EBV employs several mechanisms to catalyze the pathogenesis of
NPC by expressing type II latency genes.
Certain oncogenic pathways have been implicated in the progression of NPC induced
by EBV infection. By activating the NF-κB and Erk1/2 signaling pathways, these EBV-miR-
BART8-3p (micro-RNAs) directly target RNT38 in NPC cells, enhancing the progression
of NPC by inducing NPC cell migration, invasion, metastasis, epithelial–mesenchymal
transition, and expression of NPC metastatic proteins [41]. Other pathways mediated by
EBV in NPC include WNT/β-catenin, Janus kinase (JAK)/STAT, PI3K/Akt/mammalian
target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), and mitogen-
activated protein kinase (MAPK) pathways [42].
Mutations in oncogenes have been reported in NPC patients, but such mutations were
not found to correlate with any of the environmental and lifestyle risk factors and were
also not frequent among the majority of NPC cases [43]. In an attempt to determine if
mutations in p53 facilitate the development of malignant clones in NPC, several types
of mutations including single-point mutation, frameshifts, deletions, and duplications
were observed to be highly frequent among nude mouse-passaged tumors, and very less
Biomolecules 2022, 12, 127 4 of 17
frequent among metastatic and primary tumor, indicating that p53 mutations are less likely
to mediate initial pathogenesis of clonal outgrowth of NPC [44]. EBV, therefore, harnesses
the mechanisms involved in regulating oncogene expression and protein functions, such as
epigenetics, transcription, translation, and post-translational modifications, to deregulate
the expression and function of the various oncoproteins that facilitate NPC pathogenesis in
ways that are later discussed in this paper.
2.3. T-Cell Lymphoma
T-cell non-Hodgkin’s lymphomas (NHLs) are rare malignancies that makeup approxi-
mately 12% of all lymphomas [45], and they are mostly characterized by extranodal disease
and necrosis or apoptosis in biopsy samples [46]. T-cell lymphomas (TCLs) are grouped into
two main subtypes: peripheral T-cell lymphomas (PTCLs) and cutaneous T-cell lymphomas
(CTCLs). All TCL subtypes have distinct characteristics and require specific diagnostic and
therapeutic treatment strategies; the wide range of subtypes with varied clinical outcomes
makes the study of the disease quite challenging [47].
PTCLs are rare cancers, associated with poor prognosis [48], with few subtypes known
to have an association with EBV [49], and makeup approximately 26% of all mature T-cell
and natural killer cell neoplasms [50]. Males are at a higher risk for most PTCL subtypes [51].
Some risk factors for PTCL include smoking, alcohol consumption, a history of eczema, or
a genetic history of hematologic cancers [52]. Wang et al. further noted that there was a
correlation between reduced risk of PTCL and patients with allergies or living or working
on a farm [51].
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of PTCL, and the
pathology of the lymphoma has been associated with infectivity of EBV [53]. However, the exact
interaction between EBV and AITL remains largely unknown. Delfau-Larue et al. (2012) [54]
showed a correlation between circulating EBV DNA and the presence of circulating AITL
malignant cells, and higher levels of EBV DNA at initial presentation correlated with poorer
response to treatment [53].
Epigenetic modulations, such as histone modification and DNA methylation, have
been observed in TCL [55]; however, epigenetic modulation of EBV proteins and microRNAs
on TCL remains largely unknown [56] and, therefore, requires extensive research.
2.4. Gastric Cancers
Gastric cancer is the second cause of death resulting from cancer and ranks fourth
among all cancer incidents worldwide [57]. Out of the annual gastric cancer cases of
about 990,000 globally, approximately 780,000 patients lose their lives [58]. Factors that
have been found to increase the risk of gastric cancer include diet, smoking, alcoholism,
family history, and infections with Helicobacter pylori and Epstein-Barr virus [57,59]. The
Cancer Genome Atlas (TCGA) grouped gastric adenocarcinomas into four main categories:
EBV-associated, microsatellite instability, chromosomal instability, and genomically stable
gastric carcinomas [60]. EBV-associated gastric cancers account for 8.8% of all gastric cancer
cases [61] and are thought to result from EBV latent infection that causes abnormalities,
such as aberrant host DNA methylation [62] with the expression of the EBV latent gene,
LMP2A, in the majority of cases [63].
2.5. Breast Cancers
Breast cancer is the most diagnosed malignancy and the leading cause of cancer mor-
tality among women in the world. According to estimates by the WHO, 2.1 million women
are diagnosed with breast cancer annually. Approximately 627,000 women died from the
disease globally in 2018, accounting for approximately 15% of all deaths caused by cancer
in women [64]. Risk factors of breast cancer include age, family history, menarche, delayed
menopause, first pregnancy after 25 years of age, nulliparity, long-term consumption of
exogenous estrogens, obesity after menopause, and encountering ionizing ray [65]. EBV
has also been found to be an etiological reason for breast cancer [66]; the virus infects
Biomolecules 2022, 12, 127 5 of 17
mammary epithelial cells and has been detected in breast tissues and in human breast
milk [67]. The first positive association of EBV infection with breast cancer was reported in
1995 [68], after which multiple studies have been performed to investigate the link between
EBV and the pathogenesis of breast cancer. For example, it has been suggested that EBV
infection makes breast epithelial cells susceptible to malignant transformation through
activation of the HER2/HER3 signaling pathway [69]. On the other hand, some studies
have reported a lack of association between EBV and breast cancer [70,71]. More so, the
detection of EBV in human breast cancer biopsies tends to show some geographic bias [72]
and, hence, a general conclusion on a causative attribute of EBV in breast cancers cannot be
clearly made.
3. Key Oncoprotein and Tumor Suppressors Involved in EBV-Associated Malignancies
Tumor suppressor genes are involved in the repair of mistakes in DNA during repli-
cation, regulation of cell division, and apoptosis, and the improper functioning of these
genes leads to different malignancies [73]. Summarized in Table 1 are EBV modulators that
are associated with different malignancies.
Table 1. Tumor suppressor/oncoprotein and EBV modulators in various cancers.
Cancer Tumor Suppressor/Oncoprotein EBV Modulators
EBNA-2
Burkitt’s lymphoma c-Myc EBV-encoded micro-RNAs
BHRF1
EBV-miR-BART5-3p
EBNA 3C
p53
Nasopharyngeal carcinoma EBNA1
LMP1
EBNA2
E-cadherin LMP1
T-cell lymphoma PD-L1 [74] LMP1
LMP2A
Gastric cancers PTEN, CDKN2, CDH1, p15, p73, etc.
EBV-encoded microRNAs
Breast cancer Nm23-H1 EBNA 3C
3.1. Proto-Oncogene/Oncogene Associated with EBV-Associated Burkitt’s Lymphoma
c-Myc
Burkitt’s lymphoma is characterized by dysregulation of the c-Myc gene resulting
from c-Myc translocation into the loci of the immunoglobulin gene [75,76]. c-Myc is a
transcription factor and a DNA binding protein that when activated targets the binding
of enhancer box DNA sequences, regulating the expression of host genes [75,77]. The
c-Myc gene has two promoters: P2, which is the predominant promoter and facilitates the
transcription of the c-Myc gene; P1, which also facilitates transcription but mostly after
translocation of the gene, where transcription is under the influence of an immunoglobulin
enhancer element [78,79]. Pathways, such as PI3-K, which modulates c-Myc activity,
have been implicated in molecular and genetic pathogenesis of BL and may facilitate
the regulation of cell division and proliferation of cancer cells [75]. These pathways,
however, are highly vulnerable to EBV infections in ways that enhance the maintenance
and progression of Burkitt’s lymphoma cells.
Biomolecules 2022, 12, 127 6 of 17
3.2. Tumor Suppressor/Oncogene Associated with Nasopharyngeal Carcinoma
3.2.1. p53
Overexpression of mutant p53 has been implicated in the development of NPC fol-
lowing EBV infection [80]. p53 is a DNA-binding protein and a transcription factor that
facilitates the activation of several genes in response to stimuli such as DNA damage and
oncogene activation [81]. This protein induces cell-cycle arrest and allows for apoptosis to
occur, which is prioritized in the treatment of cancer for killing damaged or cancer cells [82].
In addition, p53 helps to maintain chromosomal integrity in cell-cycle checkpoints through
cell-cycle arrest, which allows for double-stranded break repair [83].
3.2.2. E-Cadherin
E-cadherin is a tumor suppressor and a calcium-dependent cell adhesion molecule
that plays a major role in cell-cell adhesion in epithelial tissues [84]. Loss of the protein
affects the morphology of epithelial cells and promotes metastasis in malignant cells [85].
Compared to normal tissues, E-cadherin expression was observed to be reduced in tissues
from NPC patients, suggesting that the protein plays a role in the invasion and metastasis
of cancer [86]. Though the mechanism is not fully understood, E-cadherin is inhibited by
miR-BART9, an EBV miRNA, to stimulate the formation of a mesenchymal-like phenotype
and, subsequently, promotes migration of NPC cells [87]. Migration of NPC cells is favored
by downregulation of the cadherin-catenin cell adhesion complex [88].
3.3. PD-L1 Tumor Suppressor/Oncogene Associated with T-Cell Lymphoma
Programmed cell death ligand 1 (PD-L1) has been implicated in several malignancies
including T-cell lymphoma, and has become a promising therapeutic target [89,90]. PD-L1
is a key regulator of T-cell-mediated immune response against malignancies [91]. The
binding of PD-L1 to its receptor, programmed cell death receptor 1 (PD-L1), blocks T cells
from eliminating PD-L1-containing cells, including tumor cells [92]; therefore, making
PD-L1 a potential tumor suppressor [74].
4. Different Ways That EBV Genes/Gene Products Modulate Tumor Suppressors
4.1. Modulation of c-Myc in BL and Its Effect on Transcription
4.1.1. The Role of EBNA-2
Aside from the role of EBNA-2 in facilitating B-cell immortalization, it also serves as a
transcription activator that regulates both viral and host genes. Proto-oncogene c-Myc is
directly activated and upregulated by EBV gene product EBNA-2 (Figure 1). To understand
the modulation of c-Myc by EBNA-2, Kaiser et al. generated a construct where EBNA-2
was fused with estrogen receptor (ER-EBNA-2) [93]. ER-EBNA-2 was activated by estrogen
stimulation. It was shown that the regulation of c-Myc expression occurs at the level of
transcription and was observed when c-Myc RNA levels increased sharply over 2 h in the
presence of cycloheximide, a translation inhibitor, as opposed to a gradual increase over
6 h in the absence of the inhibitor [93]. The increased c-Myc expression in the presence of
the inhibitor of de novo protein synthesis may be due to the preexisting inactive EBNA-2,
which was activated upon estrogen treatment. While EBNA-2 may be playing a key role in
the activation of c-Myc, and earlier findings have shown that c-Myc activation can occur
independently of EBNA-2 [94].
Biomolecules 2022, 12, 127 7 of 17
Biomolecules 2022, 12, x FOR PEER REVIEW 7 of 18 
 
 
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exapcrteisvsaetde athseB MARYTC- ApamthiRwNayA w[1a0s8 d].emmioRnNstAraBteAdR dTusrainreg EEBBVV stiynpgele-I- sltartaenndcyed a,ftneorn p-creoddiicntgion 
Biomolecules 2022, 12, 127 8 of 17
messenger RNAs that are involved in post-translation regulation of both EBV and host
gene expression [108]. Six different splicing forms of EBV miRNA BART have been identi-
fied and some have been found to be upregulated in response to EBV reactivation [109].
EBV latent infection has been shown to regulate several host genes that are involved in
proliferation, apoptosis, cell survival, and gene expression. Studies of the AGS cell line
have shown that 53 and 101 genes were upregulated and downregulated, respectively, by
approximately two-fold following latent EBV infection [40].
Using a Myc-responsive luciferase reporter, the ability of EBV BART miRNA to activate
the MYC pathway was demonstrated during EBV type-I latency after prediction with
bioinformatics tools [40]. The study also found that Max-interacting protein 1 (MXI1),
a protein that negatively regulates MYC activation (translocation), was downregulated
and partially accounted for the activation and increased activity of MYC following EBV
infection (Figure 1) [40].
4.1.3. Epigenetic Effect of EBV Modulation of c-Myc
EBV-induced epigenetic effect becomes a priority in the pathogenesis of BL, having
been discovered that EBV-positive BL has fewer mutations compared to EBV-negative
BL [110]. Both EBV miRNA and MYC have been found to contribute to the regulation
of miRNA-29 in BL cells [111]. Inhibition of EBV-miR-BART6-5p altered the expres-
sion of miRNA-29 in BL cells, whereas miRNA-29 expression was regulated by MYC
through epigenetic methylation of the promoter and enhancer sequences of miR-29a/b1
and miR-29b2/c genes.
Akata BL cells without the EBV genome were used to demonstrate that EBV contributes
to tumorigenesis in BL cells by regulating the expression of c-Myc [112]. When type-I latency
was re-established in the EBV negative Akata cells, tumorigenesis was restored, and an
increased resistance to apoptosis under growth limiting conditions was observed. Higher
levels of Bcl-2 as well as an EBV-dependent decrease in c-Myc proteins were associated
with the observed anti-apoptotic effect of EBV [112].
4.2. Modulation of p53 and E-Cadherin in Nasopharyngeal Carcinoma
4.2.1. The Role of miRNAs in EBV-Induced Transcriptional Regulation of p53
EBV-miR-BART5-3p targets the 3′-untranslated regions of p53, suppresses expression,
and significantly decreases p53 mRNA [113]. Aside from targeting mRNA, EBV-miRNA5-3p
also facilitates the degradation of the p53 protein, a process that leads to the inhibition of
cell cycle arrest and apoptosis and enhances the progression of NPC [113].
4.2.2. The Role of EBNA 3C in EBV-Induced Post-Translational Modification of p53
The N-terminal domain of EBNA 3C binds directly to the C-terminal DNA-binding do-
main of p53, suppressing the apoptotic and transcriptional activities of the oncoprotein [114].
The C-terminal domain regulates the sequence-specific binding of core p53, and non-specific
binding of double-stranded DNA to the C-terminal domain has been shown to inhibit
sequence-specific binding of the core domain of p53 [115]. The data suggest that dysregu-
lated binding of the C-terminal domain can impair the function of p53 (Figure 2).
Studies have shown that EBNA 3C recruits the SCFSkp2 E3 ubiquitin ligase complex
to enhance the degradation of regulators of the cell cycle including retinoblastoma and
p27KIP [114,116]. The C- and N-terminals of EBNA 3C possess deubiquitinating activity
and can induce self-deubiquitylation or deubiquitinates murine double minute 2 (Mdm2) to
produce a stable Mdm2. Coimmunoprecipitation experiment targeting EBNA 3C confirmed
the formation of stabilized ternary complex, where EBNA 3C uses its N-terminal domain
to bind simultaneously to human Mdm2 and p53 [117]. The authors showed that EBNA 3C
promotes the degradation of p53 indirectly by (1) stabilizing Mdm2 and (2) enhancing the
E3 ligase activity of Mdm2. In addition, EBV can induce degradation of phosphorylated
p53 independent of Mdm2 by harnessing a ubiquitin–proteosome pathway that is induced
during the lytic stage of viral replication where DNA damage occurs [118] (Figure 2).
Biomolecules 2022, 12, x BFiOomRo lPecEuEleRs  2R0E22V,I1E2W, 1 27 9 of 18 9 of 17
 
 
Figure 2. A modeFli gsuhroew2i.nAg mthoed reol lseh oowf iEnBgVth geernoele porfoEdBuVctgs einne tphreo druecgtusliantitohne roefg nualastoiopnhaorfynnagsoepalh aryngeal
carcinoma. EBNA-1 interacts with USP7 and indirectly reduces the stability of p53, and the unstable 
carcinoma. EBNA-1 interacts with USP7 and indirectly reduces the stability of p53, and the unstable
p53 is degraded. EBNA-3 binds with p53 to inhibit apoptosis and favors cell proliferation. In 
p53 is degraded. EBNA-3 binds with p53 to inhibit apoptosis and favors cell proliferation. In addition,
addition, BART5-3p is involved in the degradation of p53 mRNA and downregulates the expression 
BART5-3p is involved in the degradation of p53 mRNA and downregulates the expression of p53.
of p53. The broken arrow represents the indirect activity of EBNA1 resulting in unstable p53. The 
The broken arrow represents the indirect activity of EBNA1 resulting in unstable p53. The solid
solid arrows show the direction of the associated pathways. 
arrows show the direction of the associated pathways.
4.2.3. EBV-Induc4e.2d.3 P. oEsBtV-T-IrnadnuscleadtioPnosatl- TMraondsliafitcioantiaolnM oofd pifi5c3a:t iTohneo Rf po5le3 :oTfh EeBRNolAe1o f EBNA1
EBNA1 binds cEoBmNpAe1titbiivnedlsy cwomitphe thitiigvhe lyspweictihfichiitgyh tsop eucbifiiqciutyititno-supbeiqciufiitci np-srpoeteciafisce p7r otease 7
(USP7) at the sam(UeS Psi7t)ea wt thheersea UmSePsi7t ebwinhdesr etoU sStPa7bbiliinzdes pt5o3s t[a1b5i]li azendp5, 3as[ 1a5 ]reasnudl,ta, spa53re issu mlt,opr5e3 is more
likely to remainl iukbeliyqutoitrienmataeind,u mbiqaukiitninga itte du,nmstaakbinleg. iWt uinthst arbelsep. eWcitt htor eNspPeCct ctoelNlsP, Ca dceellcsr,eaadsee crease in
in p53 levels in pN5P3Cle vceellslsi nthNaPC cells that are expressing EBNA-1 compared to nobeen observed,ts aurgeg eesxtpinrgestshiantgt hEeBinNteAr-fe1r ecnocmepoaf rEeBdN tAo -n1oinn-UeSxPp7r
ne-sesxpintein
ressing cells has
ragc tcieolnlsw ith p53
has been observceodu,l dsusgugpepsrteisnsga pthopatto tshise [i1n1t9e]r. ference of EBNA-1 in USP7 interaction with 
p53 could suppress apoptosis [119]. 
4.2.4. The Role of LMP1 in EBV-Induced Post-Translational Modification of p53
4.2.4. The Role of LMCPo1n tirna rEyBtVo-tIhnedduecgerda dPaotsivt-eTerfafencstlaotfioEnBaNl AM1oadnidfiEcaBtNioAn3 oCf opn53p 53, LMP1 accumu-
Contrary tloa tetshaen ddpehgoraspdhaotirvyela teesffpe5c3t [1o2f0 ]E. BLMNAP11i natenrdac tEs BwNithAt3uCm oornn ecpr5o3s,i s fLaMctoPr1r eceptor-
accumulates andas spohcoiastpedhofarcytloarte2s( TpR5A3 F[21)2t0o].i nLcMreaPs1e ipn5t3eraaccctusm wuliathti otnumviaorK n63e-clrinokseisd fuabcitqouri tination
while suppressing E3 ligase–MDM2-mediated ubiquitination [120]. These processes allow
receptor-associaLteMdP 1fatoctmoro d2u la(tTeRthAeFf2u)n cttoio ninocf rpe5a3sbey psu5p3p raecscsuinmg uaplaotpiotons isvainad Kpr6e3v-elinntiknegdc ell cycle
ubiquitination wahrrielset sinudpupcreedssbiyngp 5E33[ 1l2ig1a,1s2e2–]M. DM2-mediated ubiquitination [120]. These 
processes allow LMP1 to modulate the function of p53 by suppressing apoptosis and 
preventing cell c4y.3c.leE BaVrr-eInsdt uincedduEcpeigde nbeyti cpM53o d[1u2la1t,i1on22o]f.E -Cadherin in Nasopharyngeal Carcinoma
The Role of LMP1
4.3. EBV-Induced EpigLeMnePt1ica MctiovdautelastDioNn Aof mEe-Cthaydlhtrearninsf ienr aNseas1o,pwhhaircyhnhgyeaple Crmarectihnyolmatae s CDH-1 promoter
The Role of LMPa1n d, subsequently, leads to silencing of the expression of the E-cadherin gene [123]. By acti-
vating DNA methyltransferase 1, LMP1 activates the c-Jun N-terminal activator protein-1
LMP1 activ(aJNteKs -DANP-A1) pmaeththwyalytraanndsftehreaDseN 1M, wT1h-picrhom hoytperer1m(Pe1t)h,yinladtuecsi nCgDthHe-f1o rpmroamtioonteorf DNMT1
and, subsequently, leads to silencing of the expression of the E-cadherin gene [123]. By 
activating DNA methyltransferase 1, LMP1 activates the c-Jun N-terminal activator 
protein-1 (JNK-AP-1) pathway and the DNMT1-promoter 1 (P1), inducing the formation 
of DNMT1 and the histone deacetylase-containing transcriptional repression complex at 
the E-cadherin gene promoter [124]. The downregulation of the E-cadherin gene also 
induces cell migration, which facilitates the progression of NPC. Whole-genome profiling 
Biomolecules 2022, 12, 127 10 of 17
and the histone deacetylase-containing transcriptional repression complex at the E-cadherin
gene promoter [124]. The downregulation of the E-cadherin gene also induces cell migra-
tion, which facilitates the progression of NPC. Whole-genome profiling of NPCs has also
provided evidence from clinical tumor samples on immune escape of NPCs using host
and virial processes [125]. Constitutive activation of NF-κB due to the LMP1 expression
and genomic aberrations was observed in 90% of NPCs. The genomic aberration and the
expression of viral genes was postulated as a possible mechanism by which NPCs evade
the immune system [125].
4.4. Modulation of PD-L1 and c-Myc in T-Cell Lymphoma
The Role of LMP1
A significantly higher expression of PD-L1 at both mRNA and protein levels in SNK-6
(EBV-positive) cells compared to NK-92 (EBV-negative) cells have been reported, and a
positive correlation between EBV oncoprotein, LMP-1, and PD-L1 was identified [112].
The upregulation of PD-L1 by LMP-1 is mediated through the MAPK/NF-κβ pathway
in TCL [126]. Upon EBV infection, EBNA2 and LMP-1 viral proteins target c-Myc at the
transcription level, thereby causing c-Myc upregulated expression that eventually leads
to the constitutive transcription of surviving—an antiapoptotic molecule [127,128]. The
proliferation and overexpression of LMP-1 is postulated to be induced by the actions of
IL-2, IL-9, and IL-10 [129].
4.5. EBV Modulates Tumor Suppressor Genes in Gastric Cancers
4.5.1. The Role of LMP2A
EBV-induced methylation is the most common modulation in tumor suppressor genes
in gastric cancers [60], but the exact mechanism is not fully understood. While LMP2A can
activate DNA methyltransferase 1 (DNMT1) through STAT3 phosphorylation, it may not
be expressed in all epithelia cells of gastric cancers [130]. Methylation of both viral and
host DNA are important for the pathogenesis of EBV-associated gastric cancers [131]. In
the viral genome, methylation occurs in the latent genes, suppressing their expression and
allowing the virus to escape the attack from cytotoxic T lymphocytes. In the host genome,
tumor suppressor genes, including CDKN2, CDH1, p15, and p73 PTEN, are targeted for
methylation, which occurs at the CpG site. LMP2A expression has also been found to
upregulate the expression of DNMT3b which correlates with hypermethylation of several
gene promoters [132,133].
4.5.2. The Role of EBV-Encoded miRNAs
Elevated levels of miR-BART20-5p were found to be associated with worst survival
in patient with EBV-associated gastric cancers [134]. The EBV miR-BART20-5p directly
targets the 3′ untranslated region (3′ UTR) of Bcl2-associated agonist of cell death (BAD),
an apoptosis-inducing factor that facilitates apoptosis, leading to a significant reduction in
BAD cellular mRNA and protein levels [135]. miR-BART20-5p was observed to suppress
apoptosis and enhance cell growth, suggesting its contribution in the development and
progression of gastric cancers. miRNA-BART10-3p have also been reported to promote cell
proliferation and migration in EBV-associated gastric cancers by targeting and degrading a
member of the Dickkopf protein family, DKK1, which is a host gene involved in embryonic
development and a known antagonist of the WNT signaling pathway [136]. Another EBV
miRNA thought to promote tumorigenesis in gastric cancers is miRNA-BART1-3p, which
has been observed to degrade and suppress the levels of E2F3, a cell cycle regulator [137].
4.6. EBV Modulates Tumor Suppressors in Breast Cancer
The Role of EBNA 3C
EBNA 3C binds directly to nucleoside diphosphate kinase non-metastatic clone 23,
isoform H1 (Nm23-H1) and downregulates the enzyme to facilitate cancer cell survival
and progression [138]. Nm23-H1 is the metastasis suppressor that phosphorylates the
Biomolecules 2022, 12, 127 11 of 17
kinase suppressor of Ras to suppress MAPK signaling, leading to a downstream effect of
inhibiting cancer cell proliferation [139]. Although EBV has been detected in breast cancer
biopsies, its contribution to pathogenesis or progression of breast cancers remain unclear
and a controversy [72].
5. Expert Comments
EBV infection is highly ubiquitous, with over a 90% incidence rate globally, but it is
intriguing that EBV lies “dormant” in the latent infection stage in most infected people. The
need to understand the specific triggers of EBV re-activation in people with EBV-induced
malignancies therefore requires further investigation, and it cannot be overemphasized. The
key EBV proteins, LMP1 and LMP2, which are known to drive initiation and progression
of EBV-induced carcinomas, may offer therapeutic potential as druggable targets to stop or
regress carcinomas. Indeed, this concept has been explored experimentally by employing
affibodies (small affinity proteins of approximately 6.5 kDa) that are capable of inhibiting
the phosphorylation of AKT and thereby blocking the nuclear translocation of b-catenin
and eventually terminate c-Myc oncogene expression [140].
The specific host defense mechanisms that keep EBV in latent infection and prevent
reactivation in asymptomatic EBV-infected people require further investigation. A clear
understanding of such mechanisms will guide the rational development of preventive and
therapeutic interventions against EBV-induced malignancies.
Questions yet remain about the specific contribution of environmental triggers or
microbiome indicators for EBV reactivation in people with EBV-induced malignancies.
Preliminary studies have indicated exposure to solvents, such as acetone and consumption
of salted fish, as possible contributors to some EBV-induced malignancies [141,142]. Such
claims need to be further investigated and validated to proffer concrete healthcare and
policy directions.
6. Conclusions
The key protooncogenes and tumor suppressors identified in various EBV-associated
malignancies are c-Myc, p53, E-cadherin, and PD-L1. The viral proteins EBNA 2, EBNA
3C, LMP1, and EBV BART5 miRNA were found to modulate host proteins in associated
malignancies. This review discussed the different molecular mechanisms by which EBV
modulates different tumor suppressors and serves as comprehensive literature to inform
future research.
Author Contributions: Conceptualization, O.Q. and A.O.F.; literature search, A.O.F., E.A.O. and
M.B.Y.; data extraction and original draft preparation, A.O.F., M.B.Y., E.A.O. and S.M.A.; writing–
review and editing, A.O.F., M.B.Y., E.A.O., S.M.A. and O.Q.; supervision, O.Q. All authors contributed
to the important intellectual content presented. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was supported by funds from World Bank African Centres of Excellence grant
(ACE02-WACCBIP: Awandare) and a DELTAS Africa grant (DEL-15-007: Awandare). The DELTAS
Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Al-
liance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership
for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from
the Wellcome Trust (107755/Z/15/Z: Awandare) and the UK government. The views expressed in
this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Well-
come Trust, or the UK government. S.M.A was supported by a WACCBIP DELTAS PhD fellowship;
M.B.Y. and A.O.F. were supported by the WACCBIP ACE PhD fellowship.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Biomolecules 2022, 12, 127 12 of 17
Abbreviations
EBV Epstein-Barr virus
LMPs Latent membrane proteins
EBNAs Epstein-Barr virus nuclear antigens
NPC Nasopharyngeal carcinoma
IKK Inhibitory-κB kinase
NF-κB Nuclear factor kappa B
CTARs C-terminal activation regions
STAT Signal transducer and activator of transcription
PI3K Phosphatidylinositol 3-kinase
BL Burkitt’s lymphoma
UICC Union for International Cancer Control
AJCC American Joint Committee on Cancer
TNM Tumor, node, and metastasis
JAK Janus kinase
mTOR Mammalian target of rapamycin
EGFR Epidermal growth factor receptor
MAPK Mitogen-activated protein kinase
NHLs Non-Hodgkin’s lymphomas
TCLs T-cell lymphomas
PTCLs Peripheral T-cell lymphomas
CTCLs Cutaneous T-cell lymphomas
AITL Angioimmunoblastic T-cell lymphoma
PD-L1 Programmed death-ligand 1
PTEN Phosphatase and tensin homolog
CDKN2 Cyclin-dependent kinase inhibitor 2
Myc Master regulator of cell cycle entry and proliferative metabolism
Bcl-2 B-cell lymphoma 2
Mdm2 Mouse double minute 2 homolog
USP7 Ubiquitin-specific-processing protease 7
TRAF2 Tumor necrosis factor receptor-associated factor 2
DNMT1 DNA methyltransferase 1
DKK1 Dickkopf protein family
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