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Viruses are always dependent on their host in many ways. They especially rely on the cellular machinery of the host cell for their replication. In this regard, epigenetic regulation is one of the influential factors during viral infections. Hepatitis B virus (HBV) is involved in developing hepatocellular carcinoma (HCC) by different mechanisms. Both the HBc and HBx viral proteins are able to interfere with the host cell epigenetic machinery in different ways. While the role of HBc has not yet been defined in detail, HBx has been shown to have multiple effects on the host epigenetic machinery, including interaction with methyltransferases (DNMTs), methyltransferases (HMTs), histone deacetylases (HDACs), histone acetyltransferases (HATs), histone deacetylases (HDACs), m6A modification, and MiRNA. Also, it impairs the immune cell function to modulate the expression of host genes associated with HBV-induced HCC. Therefore, this chapter aims to provide an overview of the epigenetic regulation in HBV-related HCC.
Department of Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Zahra Ramezannia
Department of Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Arastoo Kaki
Faculty of Medicine, Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences, Hamadan, Iran
Somayeh Shokri*
Department of Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
*Address all correspondence to: somayehshokri1986@gmail.com
1. Introduction
Hepatitis B Virus (HBV) is a major cause of liver disease, including liver inflammation, cirrhosis, and hepatocellular carcinoma (HCC). It is an enveloped virus has a partially double-stranded DNA genome and belongs to the Hepadnaviridae family within the genus Orthohepadnavirus. The worldwide infection of HBV is estimated to affect over 2 billion individuals. Among these, more than 350 million people are afflicted with chronic HBV infection, a severe condition that is often associated with cirrhosis and liver cancer. HCC is one of the most common liver cancers in humans, which accounts for about 90% of primary liver cancer [1, 2]. Recently, evidence has pinpointed an interplay between such epigenetic alterations and the outcome of human viral infection. Some viruses like HBV exhibit epigenetic mechanisms to survive and propagate in their host which can influence the function of immune cells and the release of inflammatory molecules [3].
Epigenetics is the science that refers to the study of dynamic heritable changes in gene expression that are not due to modification of the DNA sequence. Epigenetic mechanisms regulate chromatin conformation and recruitment of the transcriptional machinery as well as regulatory molecules, thereby modulating gene expression [4]. In this chapter, we describe the predominant forms of epigenetic regulation in the development of HBV-related HCC.
Epigenetics studies inheritable modifications in gene activity that do not involve changes to the DNA sequence. These alterations have a significant impact on several biological functions such as growth, illness, and the aging process [5]. Numerous epigenetic mechanisms have been discovered, such as DNA methylation, histone modifications, and non-coding RNAs.
DNA methylation in CpG islands of promoter sequences can suppress gene activity by blocking transcription factor binding, inhibiting gene expression [6]. DNA methylation, facilitated by DNA methyltransferases (DNMTs), involves transferring a methyl group from S-adenyl methionine to a cytosine residue, forming 5mC. Two members of this family, DNMT3a and DNMT3b, can introduce a new methylation pattern to DNA that has not been modified before, hence they are referred to as de novo DNMTs. Conversely, DNMT1 has a distinct function in DNA replication, replicating the accurate methylation pattern from the parent strand to the daughter strand [7]. DNA methylation is important for cell differentiation and embryo development. It can also impact gene expression [8].
Similar to DNA methylation, posttranslational modifications of histones do not alter the DNA nucleotide sequence, but they can change its accessibility to the transcription machinery. There are various known types of histone modifications, including acetylation, methylation, phosphorylation, and ubiquitination. These are the most extensively researched and are of significant importance in regulating chromatin structure and its transcriptional activity [9, 10, 11]. Histone acetylation is regulated by two enzyme groups: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs transfer acetyl groups to histone lysine residues, leading to reduced histone-DNA interaction and increased transcriptional accessibility. HDACs remove acetyl groups, inhibiting gene expression [9, 12]. Histone methylation is facilitated by histone methyltransferases (HMTs) like lysine methyltransferases (KMTs) and arginine methyltransferases (PRMTs), while demethylation is carried out by histone demethylases (HDMs). Methylation of histone lysine or arginine indirectly affects the binding of regulatory proteins to the chromatin and leads the gene expression, unlike acetylation [13, 14]. The state of histone phosphorylation is regulated by two distinct enzymes that operate in contrasting ways. Kinases are responsible for the addition of phosphate groups, whereas phosphatases are involved in their removal [15, 16]. There are at least three recognized roles of phosphorylated histones: they participate in DNA damage repair, manage chromatin compaction related to mitosis and meiosis, and oversee transcriptional activity, much like histone acetylation [17, 18]. H2A and H2B represent two of the most prevalent ubiquitinated proteins found in the nucleus. Monoubiquitination of Histone 2A (H2Aub) is commonly linked with the silencing of genes. On the other hand, the monoubiquitination of Histone 2B (H2Bub) is generally associated with the activation of transcription. Polyubiquitination serves as a marker for protein degradation or activation within specific signaling pathways [15, 19].
Non-coding RNAs, also known as non-encoding RNAs, do not get translated into proteins. They can be classified into two main types: housekeeping non-coding RNAs and regulatory non-coding RNAs. The regulatory RNAs are further categorized into two groups based on their size: short-chain non-coding RNAs (which include siRNAs, miRNAs, and piRNAs) and long non-coding RNAs (lncRNAs) [16, 20]. SiRNA is derived from long double-stranded RNA molecules, generated from viral replication, gene transcription, or transposon activity. These molecules are cleaved into 19–24 nucleotide fragments by the Dicer enzyme. They function by binding to Argonaute (AGO) proteins. SiRNA can cause gene silencing in cells through DNA methylation and histone modification processes [21]. miRNAs, short RNA (22 nt) molecules encoded in the genome, impact gene expression by binding to target mRNAs and hindering their stability or translation [22]. miRNA binding to mRNA in full complementarity can result in target degradation. Binding with partial complementarity, especially in 3’ UTR regions, leads to translational inhibition of target genes through an unresolved mechanism. It is predicted that each miRNA has multiple targets, and each mRNA may be regulated by more than one miRNA [23]. P-element-induced wimpy testis (PIWI)-interacting RNAs, or piRNAs, regulate gene expression by attaching specific nucleotides to gene promoters. They control DNA methylation, silence transposable elements, and modify chromatin in the epigenetic process [24]. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, cannot code proteins, and are transcribed by RNA polymerase II (RNA Pol II) [25]. They can either enhance or inhibit transcriptional activity by managing the placement of histone marks on chromatin regions. It is believed that many lncRNAs involved in epigenetic regulation interact with the polycomb repressive complex 2 (PRC2), which applies the repressive histone 3 Lys 27 trimethylation (H3K27m3) histone mark, with the aim of suppressing gene transcription [26].
In summary, epigenetic processes have a significant impact on gene expression, tissue development, and disease progression. Incorrect epigenetic modifications can lead to congenital abnormalities, pediatric illnesses, or manifestations of diseases at different stages of life. Additionally, epigenetic processes play a crucial role in governing the development and adjustments throughout an organism’s lifespan, and any changes to these mechanisms can potentially give rise to a range of disorders, including cancer.
Hepatitis B virus (HBV) is a small DNA virus that has the ability to enter hepatocytes via a receptor-mediated mechanism. This involves the binding of envelope proteins PreS1 and PreS2 to the receptor sodium taurocholate cotransporter polypeptide (NTCP) located on the surface of hepatocytes.
It releases relaxed circular double-stranded DNA (rcDNA) into the nucleus, where it undergoes complete repair to form covalently closed circular DNA (cccDNA) [27]. The cccDNA exists as an episomal DNA structure, arranged into a minichromosome through the interaction of histone and non-histone proteins. The cccDNA serves as the persistent form of the viral genome and the transcription template for virus reproduction [28]. The cccDNA employs the cellular transcriptional machinery to generate all viral RNAs needed for protein synthesis and viral replication [29]. The cccDNA plays a crucial role in chronic infection, and the epigenetic alteration of cccDNA influences viral replication and prognosis in individuals with chronic HBV infection [28]. Investigating the underlying mechanisms of chronic liver disease progression at the epigenetic and cellular level holds significant significance. Epigenetic regulation plays a significant role in the advancement of chronic liver infection induced by hepatitis B, as it influences the expression of cellular genes. A number of epigenetic modifications have been recently identified which may control the progression of chronic liver disease. In this regard, Zeybel et al. indicated that methylation of Homeobox A2 (HOXA2) was elevated during the advancement of chronic liver disease induced by hepatitis B. They identified three loci in the HDAC4 and HOXA2 genes that were found to have hypermethylation, while a CpG site in the Protein Phosphatase 1 Regulatory Subunit 18 (PPP1R18) gene showed lower methylation levels in cases of HBV-associated advanced liver fibrosis [30]. Furthermore, research carried out by Kaneto et al. and Vivekanandan et al. on the epigenetics of HBV chronic liver disease has highlighted the significance of DNA methylation in the progression of the disease [31, 32]. Enhancing our comprehension of the epigenetic mechanisms implicated in HBV chronic infection could facilitate the advancement of therapeutic strategies targeting the inactivation of cccDNA. Research suggests that epigenetic treatments could offer a hopeful strategy for addressing chronic viral infections like HIV and EBV [33].
In addition to cellular factors, both the viral core (HBc) and HBx proteins play crucial roles in the biology and activity of cccDNA. The viral core protein seems to primarily function as a structural element of the cccDNA minichromosome, leading to the decreased nucleosomal spacing on the cccDNA in contrast to cellular chromatin [34]. The HBx protein plays a crucial role in enhancing cccDNA-mediated viral transcription. Belloni and colleagues could provide the first in vitro evidence that HBx is recruited onto the cccDNA minichromosome, whereas an HBV X-minus mutant showed reduced replication capability [35]. The HBx protein induces the transcription of host genes through direct interaction with nuclear transcription factors or by triggering different signal transduction pathways in the cytoplasm, demonstrating its significant role as an epigenetic modifier [28]. The recruitment of HBx to the cccDNA minichromosome provides strong evidence indicating that HBx is crucial in regulating cccDNA-driven HBV transcription at an epigenetic level [36].
Epigenetic regulation mechanisms, which include histone modifications, methylation, phosphorylation, ubiquitination, and many others, can affect cccDNA activity [37]. Methylation of the CpG islands on HBV cccDNA regulates HBV replication and gene expression. The HBV cccDNA contains three CpG islands (I-III) [28]. Zhang et al. demonstrated that CpG Island 1 is seldom methylated but methylation of CpG Island 2 is associated with low viremia [38]. Furthermore, methylation of CpG Island 3 may contribute to a lower serum HBsAg level and is correlated with hepatocarcinogenesis [38, 39]. Methylation is catalyzed by the DNMTs and HBx induces the expression of DNMTs. Consequently, prolonged expression of HBx is likely to promote epigenetic changes that can impact both the viral life cycle and the host cell [40].
Furthermore, it has been made clear that histone modifications of the cccDNA may regulate its transcription [41]. Research conducted on hepatoma cell lines has revealed that the transcription of cccDNA is regulated by the acetylation levels of histones 3 and 4 (H3 and H4) bound to cccDNA. Conversely, findings from liver biopsies of individuals infected with HBV have suggested that hypoacetylation and the recruitment of HDAC1 to cccDNA are associated with lower HBV viremia levels. In accordance with this, the association between higher levels of HBV replication and the acetylation of cccDNA-bound H4 has been demonstrated [42]. The process of histone acetylation and the activation of cccDNA transcription require the recruitment of HATs, including CREB-binding protein (CBP), p300, and the p300/CBP-associated factor (PCAF) onto the cccDNA. It has been previously stated that the HBx protein plays a crucial role in facilitating the recruitment of these HATs to epigenetically regulate cccDNA function [35]. Accumulating evidence indicates that epigenetic mechanisms in HBV infection may contribute to HCC development.
4. Epigenetic regulation in the development of hepatitis B virus-related hepatocellular carcinoma
HCC is the third cause of oncological death worldwide, with an overall 5-year survival of less than 20% [43, 44]. HBV affects around 300 million people worldwide and stealthily maintains a delicate balance between viral replication and evasion of the host immune system, which has been etiologically implicated in approximately 80% of total HCC incidence [45, 46]. Studies have shown that epigenetic regulation plays an important role in virus persistence and the development of HBV-HCC infection [47]. HBx proteins are known to interact with viral and cellular proteins and can initiate a wide range of epigenetic changes implicated in hepatocarcinogenesis including DNA methylation, histone modifications, chromatin remodeling, microRNA (miRNA) dysregulation, and m6A modification [48].
As is known, DNA methylation plays a very important role in a number of key processes including gene expression, chromatin stability, and genetic imprinting [49]. DNA methylation patterns are catalyzed by a family of DNA DNMTs, including DNMT1, DNMT3A, and DNMT3B. Increasing evidence suggests that epigenetic disorders are partly induced by dysfunctional DNMTs which are involved in tumor transformation and progression [50]. Persistent HBV infection causes significant upregulation of DNMT 1, 2, and 3 expressions [32]. In this regard, evidence indicates that alteration of host DNA methylation occurs early in HBV infection and may contribute to HCC development [40]. The HBx protein acts as an epigenetic modifying factor in the human liver and upregulates the expression of DNMT1 and DNMT3A, and upregulation of DNMTs was observed in HBV-associated HCC tissues compared with adjacent normal liver tissues [51].
Metallothionein-1F (MT1F) is a putative tumor suppressor and has been demonstrated to suppress the growth of HCC cells [52]. The HBx controls epigenetic changes through its direct interaction with DNMT3A, facilitating the recruitment of DNMT3A to the MT1F promoters [53]. Dong et al. revealed a down-regulated expression of MTIF in liver cancer tissue that supports the inhibited function of MT1F in cancer growth. This finding emphasizes the potential importance of MT1F in gene therapy for HCC [52]. Interleukin-4 receptor (IL4-R) is a receptor that binds to IL-4, a cytokine that plays important roles in immune response, cell growth, apoptosis, and various diseases such as allergies, anti-parasitic infections, and autoimmune disorders. The downregulation of IL-4R induced by HBx through the promotion of DNMT3A could serve as a defensive mechanism against host immune responses. This is supported by the role of IL-4 in inducing apoptosis in human hepatocytes via a Fas-independent pathway [54].
The HBx protein triggers hypermethylation of the retinoic acid receptor beta2 (RARβ2) gene by increasing DNMT1 and 3A activities while reducing the expression of RARβ2 protein. The RARβ2 interacts with and deactivates the E2F Transcription Factor 1 (E2F1), crucial for cell cycle progression. Down-regulation of RARβ2 protein expression leads to E2F1 activation, which abolishes the ability of retinoic acid to regulate the expression of G1 checkpoint regulators, leading to up-regulation of cyclin-dependent kinase inhibitor 2A (p16), cyclin-dependent kinase inhibitor 1 (p21), and kinase inhibitory protein 1 (p27) proteins. E2F1 activation promotes uncontrolled cell growth, contributing to carcinogenesis [55, 56].
CDH6 encodes a classical cadherin of type II and facilitates cell-to-cell adhesion through homophilic interactions. It is prominently expressed in cell lines of HCC, but not in the liver. Moreover, it is believed to play a role in the metastasis and invasion. In contrast, HBx induces the transcription of CDH6 by displacing DNMT3A from their promoters (63).
Tumor-suppressor genes (TSGs) or anti-oncogenes usually encode negative regulators that protect the cell from proceeding toward cancer [57]. Previous studies have also indicated that the abnormality of key DNA methylation enzymes such as DNMTs leads to the inactivation of TSGs, thereby expediting the progression of liver cancer [58]. The HBx induces hypermethylation of TSGs via increased expression of DNMTs [59]. The findings from a research study revealed that the overexpression of HBx in HK-2 cells leads to the induction of hypermethylation in the promoter region of the phosphatase and tensin homolog (PTEN), a well-known TSG. Additionally, the abnormal methylation changes in genes associated with tumors may result in the suppression of TSGs or the activation of oncogenes, thereby playing a role in the initiation and progression of liver cancer [60]. The present data may provide a theoretical basis for the development of a specific drug from DNMT inhibitors, effectively inhibiting HBV replication and impeding the progression of HCC.
HBV DNA methylation including cccDNA affects the viral replication and protein expression in the course of infection and is a more frequent occurrence in cases of HCC compared to those with chronic hepatitis B (CHB) and cirrhosis. Three typical CpG islands within the HBV genome are the common sites for methylation [51]. Lee et al. showed that wild-type HBV cccDNA containing hypermethylated CpG island II replicated more effectively compared to the HBx-null mutant cccDNA with hypomethylated CpG island II [61]. NRE binding protein (NREBP), also known as the NRE binding protein, acts as a repressor by binding to a particular site on the NRE. This binding inhibits the synthesis of pgRNA from the core promoter. Consequently, the overexpression of NREBP suppresses the transcription of pgRNA from cccDNA, leading to a decrease in the production of HBV virions. The DNA methylation of C-1619 within the NREBP binding site plays a crucial role in stimulating HBV replication through the HBx [62]. The growth, metastasis, and drug resistance in various human tumors are facilitated by the activation of signaling pathways related to Insulin-like growth factor (IGF). The actions of IGF are regulated by Insulin-like growth factor binding protein (IGFBP-3), which binds to IGF and influences its functions [63]. The HBx suppresses the expression of IGFBP-3 by de novo DNA methylation [64]. Downregulation of IGFBP-3 levels can lead to the activation of PI3K/Bcl-2 and RAS/JUN signaling pathways, promoting tumor progression [65].
The modification of histones is all reversible and serves as good epigenetic indicators of chromatin state associated with gene activation or repression. They include acetylation, methylation, phosphorylation, sumoylation, ubiquitination, ADP-ribosylation, deamination, and the non-covalent proline isomerization (histone H3) [53, 66]. Several enzymes catalyze these processes, including HATs, HDACs, HMTs, and histone demethylases (HDMTs) [53]. HDACs remove acetyl groups from lysine residues at the N-terminal ends of histone proteins, restoring the positive charge of lysine. This leads to chromatin condensation and suppression of gene expression [67]. Therefore, HDACs are crucial in regulating chromatin accessibility throughout processes such as transcription, replication, recombination, and repair [68]. Studies have shown that the disruption of HDACs activity can impact viral tumorigenesis through various mechanisms, including the manipulation of TSGs and viral gene expression [69]. As mentioned above, the persistence of HBV cccDNA and its role as the transcriptional template for all viral RNAs pose a significant challenge for patients with chronic HBV infection, as it leads to the reactivation of HBV infection. The HBx protein by recruiting HDAC1/2 to cccDNA and via elevated levels of p21 and p27 proteins halts cell cycle progression [70, 71]. The transcriptional repression of IGFBP-3 occurs as a result of the formation of the HBx/ HDAC1 complex [72]. Romidepsin (FK228) and vorinostat (SAHA), which are HDAC inhibitors, enhance HBV replication by halting the progression of the cell cycle at the G1 phase and inhibiting its transition to the S phase. This discovery could potentially offer valuable insights into the development of more effective therapeutic approaches for the prevention and treatment of HCC [73].
Conversely, acetylation of histones by HATs on histone proteins by transferring an acetyl group from acetyl CoA to lysine residues, leads to an open state of chromatin and allows access to transcription factors and promotes gene transcription [74]. Acetylation of histone H3 plays a role in the replication of HBV DNA. Hyperacetylation leads to increased HBV replication [75]. It has been reported that HBx activates HBV transcription by recruiting PCAF/GCN5, p300, and CBP acetyltransferases onto cccDNA. Additionally, HBx inhibits cellular factors, such as the PP1/HDAC1 complex, that are involved in chromatin regulation [76]. HDAC1 and protein phosphatases-1 (PP1) collaborate in the process of histone deacetylation and CREB dephosphorylation [77]. Figure 1 shows the signaling pathways that can be affected by HATs. Taken together, HATs/HDACs possess the ability to regulate modifications in a reversible manner, making the pursuit of epigenetic drugs as a valuable tool in fighting liver cancer quite enticing.
Figure 1.
HBx induced epigenetic expression in HBV-HCC. (For further details please refer to the text).
Histone methylation mainly occurs on histone tails of H3 and H4 which are HMTs responsible for adding methyl groups to lysine and/or arginine residues [78]. The HBx may facilitate HBV-induced HCC development by either suppressing or triggering HMTs [79]. SMYD3 plays a crucial role in the development of human cancer by methylating histone 3 lysine-4 (H3K4) and histone 4 lysine-5 (H4K5) as a methyltransferase [80]. SMYD3 expression in HCC cells is controlled by HBx, which also increases the levels of SMYD3 mRNA and protein in HepG2 cells. HBx-SMYD3 interaction could potentially lead to the activation of activator protein 1 (AP-1) signaling in HBV-infected HCC cells, with C-MYC possibly being a gene-targeted downstream [81, 82]. On the other hand, the HBx protein has the ability to counteract the inhibitory impact of histone methylation on cccDNA through the activation of an HDMT agent. HBx has the potential to enhance the repression of TSGs in HCC by promoting the trimethylation of Histone 3 lysine 9 (H3K9me3) [83]. Based on the achievements obtained, epigenetic-targeted therapy is a promising strategy for anticancer treatment (Figure 1).
miRNAs are small non-coding RNAs that act as post-transcriptional gene silencers in the HBV-HCC pathways [84]. HBx-dysregulated miRNA in HBV-HCC pathogenesis influences and is influenced by epigenetic changes to modulate both viral and host genome expression [70]. A schematic illustration of the role of miRNAs in HBV infection is shown in Figure 2.
Figure 2.
Epigenetic role of HBx dysregulated miRNA in HBV-HCC. miRNA: MicroRNA; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; EMT: epithelial-mesenchymal transition; PDCD4: programmed cell death 4; PTEN: phosphatase and tensin homolog; FOXO1: forkhead box protein O1; cyclin-dependent kinase 8; PAK2: p21-activated kinase 2; MMP: matrix metalloproteinase; SHIP1: inositol polyphosphate 5-phosphatase 1; URG11: upregulated gene 11; TGF-β: transforming growth factor-β; CUL5: cullin 5; NF-κB: nuclear factor kappa B; Nrf2: nuclear factor erythroid 2–related factor 2; NLRP3: nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3; P53: tumor protein p53; and DNMT1: DNA methyltransferase 1.
N6-methyladenosine (m6A) is a common chemical modification of mRNA and affects their splicing, nuclear export, stability, decay, and translation. The M6A modification is dynamically regulated by three enzymes, namely, m6A methyltransferases, m6A demethylases, and m6A binding proteins [85]. The addition of m6A modifications to HBV RNA can influence its stability and translation, thereby affecting viral replication and pathogenesis. In HBV infection, methyltransferase-like protein 3 (METTL3) and METTL14 are recruited by HBx [86] and HBx carries through methylation activity by interacting with METTL3 and METTL14, enhancing their nuclear import [87]. Indeed, METTL3/METTL14 are m6A RNA methyltransferases that induce the nuclear import of METTL3/14 complex leads to increasing the levels of m6A modification in viral RNAs [88]. During HBV infection, the HBx protein enhances co-transcriptional m6A methylation of PTEN mRNA, which in turn inhibits IRF-3 nuclear translocation and the transcription of IFN- β mRNA (Figure 3) [89]. Thus, HBV could promote HBV-associated hepatocarcinogenesis through m6A modification and the components of m6A modification machinery could be potential important targets for HCC treatment.
Figure 3.
The roles of m6A modification in HBV infection. The m6A modification occurs in consensus DRACH motifs of cellular and viral RNAs. The addition of m6A modifications to HBV RNA can influence its stability, nuclear export, and translation, thereby affecting viral replication and pathogenesis. HBV dramatically enhances the m6A modification of host PTEN RNA, which leads to its degradation with a corresponding decrease in PTEN protein levels. PTEN, being a tumor suppressor, its low expression may contribute to hepatocarcinogenesis associated with HBV infection.
Epigenetic changes in peripheral blood mononuclear cells (PBMC) have been associated with HBV-related liver disease progression [90]. The dysregulation of many nutrients and metabolites, including glucose, glutamine, arginine, lactate, and succinate play important roles in regulating intratumoral immune cell function by directly acting on tumor cells or by reshaping the function of tumor-infiltrating lymphocytes (TILs, for example, macrophages, NK cells, and CD8+ T cells) [91]. Macrophages play a crucial role in the context of HBV infection and epigenetic modifications. Macrophage polarization is closely linked to changes in the cellular metabolic pathways and is classified as classically activated M1 and alternatively activated M2. M1 macrophages are pro-inflammatory macrophages that are induced by microbial products and can secrete a large number of pro-inflammatory cytokines. M2 macrophages are anti-inflammatory macrophages that secrete anti-inflammatory factors. Nowadays, it is accepted that M2 macrophages have a pro-tumor role, whereas M1 macrophages have antitumor activity. Post-translational modification refers to the covalent and generally enzymatic modifications of proteins, and peptides after their biosynthesis. Histone lysine lactylation (Kla) is a new epigenetic modification that regulates gene expression in macrophages. Histone Kla via the potential histone Kla writer protein p300 promotes the expression of M2-like genes in the late phase of M1 macrophage polarization after an inflammatory response, including arginase 1 (Arg1). Dysregulation of histone Kla by lactate disrupts the balance of gene transcription and causes diseases, including cancer. HBV may promote M2 polarization of macrophages to impair the immune response of Type 1 T helper cells, resulting in persistent infection and disease progression. On the other hand, studies by other researchers have shown that in M1 macrophages, lactate stimulates gene transcription through Kla to promote homeostasis. With these findings, it can be hypothesized that HBV, via increasing lactate, leads indirectly to liver damage through Kla [92].
In addition to lactate, itacone can also be an example of the consequences of metabolic reprogramming during immunity. Itaconate is generated from the citric acid (TCA) cycle by the decarboxylation of cis-aconitate via the aconitate decarboxylase 1 (ACOD1) which is encoded by the immune response gene 1 (IRG1). Abnormal accumulation of IRG1 contributes to HCC progression by inducing the exhaustion of CD8+ T cells in the tumor microenvironment (TME) at the epigenetic level between macrophage metabolism and T-cell exhaustion [91, 93]. Considering the novelty of this idea among researchers, it seems interesting to investigate the effect of itacone on epigenetic induction in HBV infection. Taken together, the increasing knowledge about the epigenetic mechanisms and the role of their dysregulation on hepatocarcinogenesis may open new avenues for developing cancer therapy.
Epigenetic-based drugs (epidrugs) act on the enzymes necessary for epigenetic alterations. Several epidrugs have already been developed that target histone or DNA modifications. For example, some HADC inhibitors such as SAHA and FK228 is already being used in clinical trials for the treatment of lymphoma patients [94]. The Jumonji-C (JmjC) family of lysine demethylases by way of histone demethylation influence gene expression and chromatin structure [95]. Interestingly, reduced cell proliferation and induction of cell death have been shown by JmjC inhibitors cells in HCC cells [96]. In a study, Zeisel et al. described epidrugs in HBV-induced HCC patients, results are shown in Table 1 [97]. Recent findings on epigenetic changes induced by HBV will open a new way to develop new diagnoses and treatments for HCC.
Compound
Target
Model system
Decitabine
DNMTs
Cell lines
Nicotinamide
Sirt1
Mice
Resveratrol
Sirt1
Cell lines & mice
SAHA
HDACs
Cell lines & mice
TSA
HDACs
Cell lines
WDR5–0103
WDR5
Cell lines & mice
Table 1.
Epidrugs in HBV-associated HCC model systems.
DNMT: DNA methyltransferase; Sirt1: sirtuin 1; HDAC: histone deacetylase; WDR5: WD repeat domain 5; decitabine: 5-aza-2′-deoxycytidine; SAHA: Suberoylanilide hydroxamic acid; and TSA: Trichostatin A.
The prognosis of HCC depends on both the stage of the tumor and the severity of the liver function. It is projected that by 2040, 1.3 million people will die from this disease, indicating a 56.4% increase from 2020. In developing countries, the incidence and mortality of HBV-HCC is an intractable public health problem that can be limited by early detection and therapeutic options. In the last decade, our knowledge on epigenetic modifications in viral infection shows a role in the early productive infection events. Since the epigenetic processes are reversible they would also provide new molecular determinants by which host and environmental factors can regulate HBV replication and pathogenesis. It is proposed that epigenetic changes may offer a novel approach to HBV-HCC treatment. This chapter should contribute to the point of view that our understanding of epigenetic mechanisms in HBV infection will be useful as a therapeutic option in HBV-HCC.
1.Shokri S, Mahmoudvand S, Taherkhani R, Farshadpour F, Jalalian FA. Complexity on modulation of NF-κB pathways by hepatitis B and C: A double-edged sword in hepatocarcinogenesis. Journal of Cellular Physiology. 2019;234:14734-14742. DOI: 10.1002/jcp.28249
2.Adam A, Fusheini A. Knowledge, risk of infection, and vaccination status of hepatitis B virus among rural high school students in Nanumba north and south districts of Ghana. PLoS One. 2020;15:e0231930. DOI: 10.1371/journal.pone.0231930
3.Nehme Z, Pasquereau S, Herbein G. Control of viral infections by epigenetic-targeted therapy. Clinical Epigenetics. 2019;11:55. DOI: 10.1186/s13148-019-0654-9
4.Zuccarello D, Sorrentino U, Brasson V, et al. Epigenetics of pregnancy: Looking beyond the DNA code. Journal of Assisted Reproduction and Genetics. 2022;39:801-816. DOI: 10.1007/s10815-022-02451-x
5.Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes & Development. 2009;23:781-783. DOI: 10.1101/gad.1787609
6.Mattei AL, Bailly N, Meissner A. DNA methylation: A historical perspective. Trends in Genetics. 2022;38:676-707. DOI: 10.1016/j.tig.2022.03.010
7.Goto K, Numata M, Komura J-I, Ono T, Bestor TH, Kondo H. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation. 1994;56:39-44. DOI: 10.1046/j.1432-0436.1994.56120039.x
8.Suzuki MM, Bird A. DNA methylation landscapes: Provocative insights from epigenomics. Nature Reviews Genetics. 2008;9:465-476. DOI: 10.1038/nrg2341
9.Swygert SG, Peterson CL. Chromatin dynamics: Interplay between remodeling enzymes and histone modifications. Biochimica et Biophysica Acta. 2014;1839:728-736. DOI: 10.1016/j.bbagrm.2014.02.013
10.Rossetto D, Avvakumov N, Côté J. Histone phosphorylation: A chromatin modification involved in diverse nuclear events. Epigenetics. 2012;7:1098-1108. DOI: 10.4161/epi.21975
11.Healy S, Khan P, He S, Davie JR. Histone H3 phosphorylation, immediate-early gene expression, and the nucleosomal response: A historical perspective. Biochemistry and Cell Biology. 2012;90:39-54. DOI: 10.1139/o11-092
12.Nicolas D, Zoller B, Suter DM, Naef F. Modulation of transcriptional burst frequency by histone acetylation. Proceedings of the National Academy of Sciences of the United States of America. 2018;115:7153-7158. DOI: 10.1073/pnas.1722330115
13.Gulati P, Kohli S, Narang A, Brahmachari V. Mining histone methyltransferases and demethylases from whole genome sequence. Journal of Biosciences. 2020;45:1-17. DOI: 10.1007/s12038-019-9982-3
14.Li J, Tao X, Shen J, et al. The molecular landscape of histone lysine methyltransferases and demethylases in non-small cell lung cancer. International Journal of Medical Sciences. 2019;16:922. DOI: 10.7150/ijms.34322
15.Goldknopf I, Taylor CW, Baum RM, et al. Isolation and characterization of protein A24, a “histone-like” non-histone chromosomal protein. Journal of Biological Chemistry. 1975;250:7182-7187
16.Zaratiegui M, Irvine DV, Martienssen RA. Noncoding RNAs and gene silencing. Cell. 2007;128:763-776. DOI: 10.1016/j.cell.2007.02.016
17.Zhang B, Dong Q , Su H, Birchler J, Han F. Histone phosphorylation: Its role during cell cycle and centromere identity in plants. Cytogenetic and Genome Research. 2014;143:144-149. DOI: 10.1159/000360435
18.Wang Q , Wang C-M, Ai J-S, et al. Histone phosphorylation and pericentromeric histone modifications in oocyte meiosis. Cell Cycle. 2006;5:1974-1982. DOI: 10.4161/cc.5.17.3183
19.West MH, Bonner WM. Histone 2B can be modified by the attachment of ubiquitin. Nucleic Acids Research. 1980;8:4671-4680. DOI: 10.1093/nar/8.20.4671
20.Moazed D. Small RNAs in transcriptional gene silencing and genome defence. Nature. 2009;457:413-420. DOI: 10.1038/nature07756
21.Kawasaki H, Taira K. Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature. 2004;431:211-217. DOI. DOI: 10.1038/nature02889
22.Kim VN, Nam J-W. Genomics of microRNA. Trends in Genetics. 2006;22:165-173. DOI: 10.1016/j.tig.2006.01.003
23.Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136:642-655. DOI: 10.1016/j.cell.2009.01.035
24.Zhang D, Tu S, Stubna M, et al. The piRNA targeting rules and the resistance to piRNA silencing in endogenous genes. Science. 2018;359:587-592. DOI: 10.1126/science.aao2840
25.Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629-641. DOI: 10.1016/j.cell.2009.02.006
26.Trotman JB, Braceros KC, Cherney RE, Murvin MM, Calabrese JM. The control of polycomb repressive complexes by long noncoding RNAs. Wiley Interdisciplinary Reviews: RNA. 2021;12:e1657. DOI: 10.1002/wrna.1657
27.Yang Z, Sun B, Xiang J, et al. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Frontiers in Immunology. 2022;13:1018053. DOI: 10.3389/fimmu.2022.1018053
28.Hong X, Kim ES, Guo H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B. Hepatology. 2017;66:2066-2077. DOI: 10.1002/hep.29479
29.Tropberger P, Mercier A, Robinson M, Zhong W, Ganem DE, Holdorf M. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proceedings of the National Academy of Sciences of the United States of America. 2015;112:E5715-E5724. DOI: 10.1073/pnas.1518090112
30.Zeybel M, Vatansever S, Hardy T, et al. DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease. Clinical Epigenetics. 2016;8:48. DOI: 10.1186/s13148-016-0218-1
31.Kaneto H, Sasaki S, Yamamoto H, et al. Detection of hypermethylation of thep16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut. 2001;48:372-377. DOI: 10.1136/gut.48.3.372
32.Vivekanandan P, Daniel HD-J, Kannangai R, Martinez-Murillo F, Torbenson M. Hepatitis B virus replication induces methylation of both host and viral DNA. Journal of Virology. 2010;84:4321-4329. DOI: 10.1128/jvi.02280-09
33.Ramos JC, Lossos IS. Newly emerging therapies targeting viral-related lymphomas. Current Oncology Reports. 2011;13:416-426. DOI: 10.1007/s11912-011-0186-8
34.Bock CT, Schwinn S, Locarnini S, et al. Structural organization of the hepatitis B virus minichromosome. Journal of Molecular Biology. 2001;307:183-196. DOI: 10.1006/jmbi.2000.4481
35.Belloni L, Pollicino T, De Nicola F, et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:19975-19979. DOI: 10.1073/pnas.0908365106
36.Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. Journal of Hepatology. 2009;51:581-592. DOI: 10.1016/j.jhep.2009.05.022
37.Cai Q , Gan C, Tang C, Wu H, Gao J. Mechanism and therapeutic opportunities of histone modifications in chronic liver disease. Frontiers in Pharmacology. 2021;12:784591. DOI: 10.3389/fphar.2021.784591
38.Zhang Y, Mao R, Yan R, et al. Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection. PLoS One. 2014;9:e110442. DOI: 10.1371/journal.pone.0110442
39.Jain S, Chang T-T, Chen S, et al. Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues. Scientific Reports. 2015;5:10478. DOI: 10.1038/srep10478
40.Dandri M. Epigenetic modulation in chronic hepatitis B virus infection. Seminars in Immunopathology. 2020;42:173-185. DOI: 10.1007/s00281-020-00780-6
41.Shi L, Li S, Shen F, et al. Characterization of nucleosome positioning in hepadnaviral covalently closed circular DNA minichromosomes. Journal of Virology. 2012;86:10059-10069. DOI: 10.1128/JVI.00535-12
42.Pollicino T, Belloni L, Raffa G, et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology. 2006;130:823-837. DOI: 10.1053/j.gastro.2006.01.001
43.Serraino D, Fratino L, Piselli P. Epidemiological aspects of hepatocellular carcinoma. In: Hepatocellular Carcinoma. Cham: Springer International Publishing; 2023. pp. 3-9. DOI: 10.1007/978-3-031-09371-5-1
44.Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345-1362. DOI: 10.1016/s0140-6736(22)01200-4
45.Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of related factors for persistent risk of hepatitis B virus-associated hepatocellular carcinoma. Cancers (Basel). 2024;16:777. DOI: 10.3390/cancers16040777
46.Petruzziello A. Epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) related hepatocellular carcinoma. Open Virology Journal. 2018;12:26-32. DOI: 10.2174/1874357901812010026
47.Wolinska E, Skrzypczak M. Epigenetic changes affecting the development of hepatocellular carcinoma. Cancers. 2021;13:4237. DOI: 10.3390/cancers13164237
48.Agustiningsih A, Rasyak MR, Turyadi JS, Sukowati C. The oncogenic role of hepatitis B virus X gene in hepatocarcinogenesis: Recent updates. Exploration of Targeted Anti-tumor Therapy. 2024;5:120-134. DOI: 10.37349/etat.2024.00209
49.Dhar GA, Saha S, Mitra P, Nag CR. DNA methylation and regulation of gene expression: Guardian of our health. Nucleus (Calcutta). 2021;64:259-270. DOI: 10.1007/s13237-021-00367-y
50.Zhang W, Xu J. DNA methyltransferases and their roles in tumorigenesis. Biomarker Research. 2017;5:1. DOI: 10.1186/s40364-017-0081-z
51.Low WF, Ngeow YF, Chook JB, et al. Hepatitis B virus DNA methylation and its potential role in chronic hepatitis B. Expert Reviews in Molecular Medicine. 2022;25:e11. DOI: 10.1017/erm.2022.38
52.Lu DD, Chen YC, Zhang XR, Cao XR, Jiang HY, Yao L. The relationship between metallothionein-1F (MT1F) gene and hepatocellular carcinoma. The Yale Journal of Biology and Medicine. 2003;76:55-62
53.Koumbi L, Karayiannis P. The epigenetic control of hepatitis B virus modulates the outcome of infection. Frontiers in Microbiology. 2015;6:1491. DOI: 10.3389/fmicb.2015.01491
54.Zheng DL, Zhang L, Cheng N, et al. Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. Journal of Hepatology. 2009;50:377-387. DOI: 10.1016/j.jhep.2008.10.019
55.Ali A, Abdel-Hafiz H, Suhail M, et al. Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma. World Journal of Gastroenterology. 2014;20:10238-10248. DOI: 10.3748/wjg.v20.i30.10238
56.Jung JK, Park SH, Jang KL. Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor-beta2 expression via DNA methylation. The Journal of General Virology. 2010;91:493-500. DOI: 10.1099/vir.0.015149-0
57.Abreu Velez AM, Howard MS. Tumor-suppressor genes, cell cycle regulatory checkpoints, and the skin. North American Journal of Medical Sciences. 2015;7:176-188. DOI: 10.4103/1947-2714.157476
58.Sun D, Gan X, Liu L, et al. DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334. Cell Death & Disease. 2022;13:446. DOI: 10.1038/s41419-022-04895-6
59.Zhao Z, Hu Y, Shen X, et al. HBx represses RIZ1 expression by DNA methyltransferase 1 involvement in decreased miR-152 in hepatocellular carcinoma. Oncology Reports. 2017;37:2811-2818. DOI: 10.3892/or.2017.5518
60.Guan H, Zhu N, Tang G, Du Y, Wang L, Yuan W. DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis. Cell & Bioscience. 2022;12:98. DOI: 10.1186/s13578-022-00835-1
61.Lee H, Jeong H, Lee SY, Kim SS, Jang KL. Hepatitis B virus X protein stimulates virus replication via DNA methylation of the C-1619 in covalently closed circular DNA. Molecules and Cells. 2019;42:67-78. DOI: 10.14348/molcells.2018.0255
62.Zhang D, Guo S, Schrodi SJ. Mechanisms of DNA methylation in virus-host interaction in hepatitis B infection: Pathogenesis and Oncogenetic properties. International Journal of Molecular Sciences. 2021;22:9858. DOI: 10.3390/ijms22189858
63.Hua H, Kong Q , Yin J, Zhang J, Jiang Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: A challenge for cancer therapy. Journal of Hematology & Oncology. 2020;13:64. DOI: 10.1186/s13045-020-00904-3
64.Park IY, Sohn BH, Yu E, et al. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology. 2007;132:1476-1494. DOI: 10.1053/j.gastro.2007.01.034
65.Wang H, Wang H, Li K, Li S, Sun B. IGFBP-3 is the key target of Sanguinarine in promoting apoptosis in hepatocellular carcinoma. Cancer Management and Research. 2020;12:1007-1015. DOI: 10.2147/cmar.s234291
66.Kimura H. Histone modifications for human epigenome analysis. Journal of Human Genetics. 2013;58:439-445. DOI: 10.1038/jhg.2013.66
67.Seto E, Yoshida M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harbor Perspectives in Biology. 2014;6:a018713. DOI: 10.1101/cshperspect.a018713
68.Bhaskara S, Knutson SK, Jiang G, et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell. 2010;18:436-447. DOI: 10.1016/j.ccr.2010.10.022
69.Mirzaei H, Ghorbani S, Khanizadeh S, Namdari H, Faghihloo E, Akbari A. Histone deacetylases in virus-associated cancers. Reviews in Medical Virology. 2020;30:e2085. DOI: 10.1002/rmv.2085
70.Sartorius K, An P, Winkler C, et al. The epigenetic modulation of cancer and immune pathways in hepatitis B virus-associated hepatocellular carcinoma: The influence of HBx and miRNA dysregulation. Frontiers in Immunology. 2021;12:661204. DOI: 10.3389/fimmu.2021.661204
71.Wang HY, Yang SL, Liang HF, Li CH. HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways. International Journal of Molecular Sciences. 2014;15:3507-3518. DOI: 10.3390/ijms15033507
72.Schollmeier A, Glitscher M, Hildt E. Relevance of HBx for hepatitis B virus-associated pathogenesis. International Journal of Molecular Sciences. 2023;24:4964. DOI: 10.3390/ijms24054964
73.Yang Y, Yan Y, Chen Z, et al. Histone deacetylase inhibitors Romidepsin and Vorinostat promote hepatitis B virus replication by inducing cell cycle arrest. Journal of Clinical and Translational Hepatology. 2021;9:160-168. DOI: 10.14218/jcth.2020.00105
74.Xia JK, Qin XQ , Zhang L, Liu SJ, Shi XL, Ren HZ. Roles and regulation of histone acetylation in hepatocellular carcinoma. Frontiers in Genetics. 2022;13:982222. DOI: 10.3389/fgene.2022.982222
75.Zhang D, Wang Y, Zhang HY, et al. Histone deacetylases and acetylated histone H3 are involved in the process of hepatitis B virus DNA replication. Life Sciences. 2019;223:1-8. DOI: 10.1016/j.lfs.2019.03.010
76.Kim ES, Zhou J, Zhang H, et al. Hepatitis B virus X protein counteracts high mobility group box 1 protein-mediated epigenetic silencing of covalently closed circular DNA. PLoS Pathogens. 2022;18:e1010576. DOI: 10.1371/journal.ppat.1010576
77.Segré CV, Chiocca S. Regulating the regulators: The post-translational code of class I HDAC1 and HDAC2. Journal of Biomedicine & Biotechnology. 2011;2011:690848. DOI: 10.1155/2011/690848
78.Miller JL, Grant PA. The role of DNA methylation and histone modifications in transcriptional regulation in humans. Sub-Cellular Biochemistry. 2013;61:289-317. DOI: 10.1007/978-94-007-4525-4-13
79.Tian Y, Yang W, Song J, Wu Y, Ni B. Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis. Molecular and Cellular Biology. 2013;33:2810-2816. DOI: 10.1128/mcb.00205-13
80.Wu X, Xu Q , Chen P, et al. Effect of SMYD3 on biological behavior and H3K4 methylation in bladder cancer. Cancer Management and Research. 2019;11:8125-8133. DOI: 10.2147/cmar.s213885
81.Binh MT, Hoan NX, Giang DP, et al. Upregulation of SMYD3 and SMYD3 VNTR 3/3 polymorphism increase the risk of hepatocellular carcinoma. Scientific Reports. 2020;10:2797. DOI: 10.1038/s41598-020-59667-z
82.Tanaka Y, Kanai F, Ichimura T, et al. The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. Oncogene. 2006;25:633-642. DOI: 10.1038/sj.onc.1209093
83.Wang DY, Zou LP, Liu XJ, Zhu HG, Zhu R. Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. Experimental and Molecular Pathology. 2015;99:399-408. DOI: 10.1016/j.yexmp.2015.08.020
84.Sartorius K, Makarova J, Sartorius B, et al. The regulatory role of MicroRNA in hepatitis-B virus-associated hepatocellular carcinoma (HBV-HCC) pathogenesis. Cells. 2019;8:1504. DOI: 10.3390/cells8121504
85.Cai T, Atteh LL, Zhang X, et al. The N6-Methyladenosine modification and its role in mRNA metabolism and gastrointestinal tract disease. Frontiers in Surgery. 2022;9:819335. DOI: 10.3389/fsurg.2022.819335
86.Zhang Z, Gao W, Liu Z, et al. Comprehensive analysis of m6A regulators associated with immune infiltration in hepatitis B virus-related hepatocellular carcinoma. BMC Gastroenterology. 2023;23:259. DOI: 10.1186/s12876-023-02873-6
87.Moon JS, Lee W, Cho YH, Kim Y, Kim GW. The significance of N6-Methyladenosine RNA methylation in regulating the hepatitis B virus life cycle. Journal of Microbiology and Biotechnology. 2024;34:233-239. DOI: 10.4014/jmb.2309.09013
88.Wang S, Gao S, Ye W, Li Y, Luan J, Lv X. The emerging importance role of m6A modification in liver disease. Biomedicine & Pharmacotherapy. 2023;162:114669. DOI: 10.1016/j.biopha.2023.114669
89.Kim GW, Imam H, Khan M, et al. HBV-induced increased N6 Methyladenosine modification of PTEN RNA affects innate immunity and contributes to HCC. Hepatology. 2021;73:533-547. DOI: 10.1002/hep.31313
90.Li K, Qin L, Jiang S, et al. The signature of HBV-related liver disease in peripheral blood mononuclear cell DNA methylation. Clinical Epigenetics. 2020;12:81. DOI: 10.1186/s13148-020-00847-z
91.Gu X, Wei H, Suo C, et al. Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion. Nature Communications. 2023;14:8154. DOI: 10.1038/s41467-023-43988-4
92.Mahmoudvand S, Shokri S. Effect of lactate on epigenetic regulation in the development of hepatitis B virus-related hepatocellular carcinoma. Journal of Clinical and Translational Hepatology. 2022;10:786-787. DOI: 10.14218/jcth.2022.00274
93.Li Z, Zheng W, Kong W, Zeng T. Itaconate: A potent macrophage Immunomodulator. Inflammation. 2023;46:1177-1191. DOI: 10.1007/s10753-023-01819-0
94.Umehara T. Epidrugs: Toward understanding and treating diverse diseases. Epigenomes. 2022;6:18. DOI: 10.3390/epigenomes6030018
95.Vicioso-Mantis M, Aguirre S, Martínez-Balbás MA. JmjC family of histone demethylases form nuclear condensates. International Journal of Molecular Sciences. 2022;23:7664. DOI: 10.3390/ijms23147664
96.Bayo J, Fiore EJ, Dominguez LM, et al. A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets. Journal of Hepatology. 2019;71:78-90. DOI: 10.1016/j.jhep.2019.03.007
97.Zeisel MB, Guerrieri F, Levrero M. Host epigenetic alterations and hepatitis B virus-associated hepatocellular carcinoma. Journal of Clinical Medicine. 2021;10:1715. DOI: 10.3390/jcm10081715
Written By
Shahab Mahmoudvand, Zahra Ramezannia, Arastoo Kaki
and Somayeh Shokri
Submitted: 12 May 2024Reviewed: 24 May 2024Published: 23 July 2024
Open access peer-reviewed chapter - ONLINE FIRST
