Histone methylation and acetylation in cancer: mechanism, progression, and targets
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Su Bu
und
Yongfu Zhu
Abstract
Along with the continuous development of chromatin immunoprecipitation sequencing and its derivative technologies, as well as an increased understanding of epigenetic modification, the post-translational modification of histones has gradually been revealed, including their acetylation, methylation, phosphorylation, and ubiquitination, and their roles in diseases, especially cancer, have also been gradually explored. The role and regulation of histone methylation and acetylation in cancer and the mechanism of action of drugs have been thoroughly discussed. In particular, the review highlights recent advances in the development of epigenetic-targeted therapies and the challenges that remain in translating these findings into clinical applications. Research on epigenetic-targeted drugs is in its infancy, and more research in the fields of dominant biology, structural biology, and pharmacodynamics is needed. Through this review, the authors aim to provide theoretical guidance for the construction and clinical transformation of histone methylation and acetylation.
Introduction
Histones are composed of nucleosome-modulated chromatin remodeling and regulate gene expression [1]. The post-translational modification (PTM) of histone includes methylation, acetylation, ubiquitination, and phosphorylation [2]. The type of histone modifications can be regarded as a “histone code” [3]. The N-acetylation of lysine is a typical histone modification. Generally, the acetylation of histone lysine affects transcriptional activation [4]. And different methylated sites lead to different results. Histones are organized in a manner in which double-stranded DNA is wrapped around the center of a protein made up of proteins. Multiple hydrogen bonds allow DNA to bind to protein centers formed by histones in each nucleosome. In most cases, these bonds form between the amino acid backbone of the histone and the sugar-phosphate backbone of the DNA. Some hydrophobic interactions and ionic bonds are also involved. For instance, methylation of lysine K4 on H3 affects transcriptional activation [5]. The methylation of K9 or K27 on H3, as well as the methylation of K20 on H4, are both linked to transcriptional repression [2]. Additionally, Lysine contains many methylation states, including mono-, di-, or tri-methylated states. Gene expression is mainly regulated by the methylation states of Lysine. For instance, compared with the monomethylation of histone H3 lysine 9 (H3K9) at active genes, its trimethylation is usually observed at repression genes [6].
Numerous studies have demonstrated that the compounds that target the methylation and acetylation of histone represent a novel class of anti-tumor drugs. For instance, Vorinostat and Romidepsin, both histone deacetylase inhibitors (HDACis), can be used to treat cutaneous T cell lymphoma, and have been officially approved by the U.S. Food and Drug Administration (FDA) [7]. This review explores the association between histone modification and cancer development, focusing on methylation and acetylation, and discusses the potential efficacy of these modifications in cancer treatment.
Histone and epigenetic modification
DNA is packaged into nucleosomes to form chromatin or chromosomes and thus acts as a barrier for transcription [1]. Nucleosomes are composed of histones, including H2A, H2B, H3, H4, and H1. These histones can be modified by acetylation, methylation, ubiquitination, and phosphorylation [8], all of which are epigenetic modifications. The term “epigenetics” indicates a heritable alteration in gene expression by modifications, but not through a concomitant change in the primary DNA sequence. In addition to histone modifications, there are two other typical types of histone modification, including DNA methylation and RNA interference which play important roles in the regulation of gene expression and nuclear architecture.
Histone modifications play a key role in cell differentiation and organismal development [9]. It has been reported that at least 11 types of modifications can be found in over 60 different amino acid residues on histones, including (but not limited to) methylation, acetylation, formylation, sumoylation, proline isomerization, propionylation, and phosphorylation. In the nucleus of eukaryotic cells, DNA is packaged into highly tissue-rich chromatin structures. The building blocks of chromatin are known as nucleosomes and consist of 147 pairs of bases to DNA wrapped around an octameric protein complex that involves two copies of each of the four histones: H3, H4, H2A, and H2B. Histones are subject to various modifications through the addition of chemical groups to their globular domains and to the N-terminal tail protruding from the nucleic core particles. In addition, histones are predominant in their unstructured tails and are decorated with many post-translational modifications (PTM) or co-translational modifications (CTM) translational modifications on their globular domains [10]. Two major mechanisms are involved in chromatin-templated processes [11]. Firstly, histone modifications can regulate chromatin structure and access transcription factors by changing the net charge of the histone molecules or inter-nucleosomal interactions. Secondly, histone modifications can recruit protein PTM-specific binding proteins, and recognize modified histones via chromo-, bromo- and plant homeodomain (PHD) domains [12] (Figure 1).
Modifications and amino acid residues on histones.
Generally, it is thought that the PTMs of histones are located in the N-terminal tail domain of core histones. However, novel PTM sites are being continuously discovered and the globular domain of core histones is of great importance for histone-DNA and histone-histone interactions [12]. A study on the O-linked N-acetylglucosamine (O-GlcNAc) modification of histones has demonstrated that additional PTM sites can be discovered [13].
Methylation and acetylation of histone in cancer progression
Numerous studies have verified that epigenetics plays an important role in carcinogenesis. Apart from global changes in histone modifications, the epigenome can be altered during tumorigenesis [14]. The methylation and acetylation of histones have been shown to be closely associated with tumorigenesis and progression [13]. For instance, as a common type of cancer, colon cancer has shown a potential relationship with higher histone methylation activity [15].
Histone methylation and demethylation
Generally, H3K4, H3K36, H3K27, and H4K20 [16] are regarded as the best-characterized sites of histone methylation and are often located on lysine residues. In histone H3 and H4 lysine methylation, several arginine residues have been found to be overexpressed in tumors. Mutations in H3K4 methyltransferases significantly increase susceptibility to various cancers [17]. There are different methylation states, such as the most common types: mono-(me), di-(me2), and tri-(me3). They are also located in different genomic regions. For example, H3K4me1 is modified at active enhancers and H3K4me2/3 often spans the transcriptional start site of activated genes [18]. In addition, H3K9me can be observed at active genes, but tri-H3K9me is usually located in gene repression.
In recent years, studies have shown that histone methylation plays a key role in a variety of pathophysiological processes. Histone methylation can both promote and inhibit gene expression depending on the methylation site. H3K4me3 is generally associated with gene activation, while H3K27me3 is associated with gene silencing [19]. The role of these modifications in cancer, neurodegenerative diseases, and inflammatory diseases has been extensively studied. For example, aberrant expression of H3K27me3 has been implicated in the occurrence and progression of a variety of cancers. By understanding the mechanisms of these epigenetic modifications, we can develop novel therapeutic strategies to modulate aberrant gene expression patterns and improve pathophysiological states.
Histone methylation can regulate the transcriptional and post-transcriptional levels of certain core genes of tumorigenesis and immune response. For instance, low enrichment of repressive histones in the promoter regions (H3K27me3 and H3K9me3) may be associated with programmed death receptor 1 (PD-1), Lymphocyte activation gene 3 (LAG-3), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene expression in breast cancer [20]. In addition, the low abundance of H3K9me3 and H3K27me3 in the promoter region of TIM-3 and TIGIT may be associated with the upregulation of these genes in breast and colorectal cancer, respectively [21] (Figure 2). H3K9me3 is typically associated with heterochromatin and involves the recruitment of heterochromatin protein 1 (HP1), maintaining gene silencing, especially in genomic silencing regions and centromeres. H3K27me3 is mainly regulated by the polycomb repressive complex 2 (PRC2), which binds to and modifies specific gene promoters to suppress the expression of developmental and differentiation-related genes [19]. When these repressive marks are reduced in gene promoter regions, transcription factors and other activators can more easily bind to DNA, leading to gene transcription activation. This depressive effect can reduce immune inhibitory signals, promote immune evasion by tumor cells, and accelerate tumor growth and metastasis [22].
Histone methylation and demethylation.
Histone acetylation and deacetylation
As a highly reversible process, histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) [23]. HATs catalyze the lysine residues of histone acetylated at the N-terminus and lead to transcription activation [24], 25]. Deacetylation of histone is catalyzed by HDACs, which leads to the alteration of the structure of chromatin, which may dictate the accessibility of DNA to its corresponding transcription factors and co-activators.
It has been reported that the imbalance in histone acetylation or deacetylation is an important characteristic of tumorigenesis and development [26]. Relevant studies have shown that histone acetylation is often associated with gene activation, which promotes gene expression by relaxing chromatin structure and making it easier for transcription factors to bind to DNA. Aberrant regulation of histone acetylation levels is thought to be a key factor in pathophysiological processes in a variety of diseases [27]. For example, the aberrant activity of HDACs is strongly associated with the development of cancer, HDACs can limit accessibility between a transcription factor and their binding site, as well as induce the confirmation ability of closed chromatin, which leads to the inhibition of the transcription of tumor suppression and immune response genes [28], 29] (Figure 3). In addition, the role of acetylation in neurodegenerative diseases has received increasing attention, and studies have found that alterations in histone acetylation may affect neuronal survival and function [30]. These findings further underscore the importance of histone acetylation in maintaining the normal function and health of cells.
Histone acetylation and deacetylation in cancer.
The influencing mechanism of histone methylation and acetylation on cancer progression
Histone modifications act as signals for transcription factors and chromatin remodelers and can drive distinct downstream functions between histone-histone or histone-DNA interactions [31]. The misregulation of histone modifications is often associated with cancer [32]. Methylation and acetylation are the most common among the different known types of histone modification.
Histone methylation
At present, cancer research has suggested that the physiological and pathological functions of methylation focus on gene regulation, DNA recombination, and damage repair, as well as cell differentiation [33]. For instance, the disruptor of telomeric silencing 1 like DOT1L has been proven to initiate or maintain an active transcription state, involving many transcription proteins, including AF4/9/10 and ENL [34], [35], [36], [37], as H3K79 methyltransferase. A protein complex, which includes AF4, AF9, AF10, and ENL, can recruit DOT1L for methylating H3K79 in acute leukemia, which leads to the overexpression of HoxA9, HoxA7, and Meis1, all of which are leukemia-related genes [38], [39], [40], [41]. Isocitrate dehydrogenase (IDH) is another example of a regulator of histone lysine methylation. IDH is a key enzyme tricarboxylic acid cycle [42] that has been demonstrated to show recurrent mutations in various cancers, such as glioma and acute myeloid leukemia (AML) [43], 44]. It has been reported that IDH plays key roles during the early stage of cancers – Mutant IDH proteins acquire neomorphic enzyme activity to produce putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation [44]. The process of transformation of α-KG to D-2-hydroxyglutaric acid (D2HG) is catalyzed by IDH mutant enzymes [44], 45]. The relatively higher level of D2HG was found to inhibit 5-methylcytosine hydroxylases [46], resulting in genome-wide hypermethylation of histone and DNA [47], [48], [49], which blocks cell differentiation [49].
Histone acetylation
Aberrant histone acetylation modifications have been reported to be closely associated with the expression of key genes, including tumor suppressor genes and oncogenes, as well as certain regulatory genes of biology processes, including cell cycle, proliferation, metabolism, apoptosis, and DNA repair [50], 51]. For instance, in acute promyelocytic leukemia, chromosomal translocation leads to the production of fusion proteins. Then, these fusion proteins bind to retinoic acid‐responsive elements. This fusion protein has also been reported to be involved in the recruitment process of the HDAC repressor complex [52]. These changes repress the expression of genes associated with the regulation of normal differentiation and proliferation of myeloid cells [53]. Histone acetyltransferase Males absent on the first (MOF) is mainly responsible for the acetylation of histone H4K16. In humans, MOF (hMOF), is a member of the MYST family of HATs. The modulation function of MOF on estrogen receptor α (ERα) action in hepatocellular carcinoma (HCC) suggests that MOF may be a potential therapeutic target for HCC and that certain pro-apoptotic genes, such as TMS1/ASC, could be regulated by MOF-dependent H4K16ac, which is often silent in human cancers [54].
Histone modification and acetylation regulate cancer and affect progression
Methyltransferases and demethylases regulate histone methylation. Several studies have shown that histone methylation modifications are involved in cancer processes, including methyltransferases, demethylases, and methyl-lysine-binding proteins [55]. The regulation of histone methylation and demethylation can affect cancer progression. For instance, as key genes of the methylation of H3K27, EZH2 has been proven to function as an oncogene in breast and hepatocellular cancer [56], 57]. The overexpression of EZH2 promotes the development of breast and prostate cancer [58], and certain miRNAs control the overexpression of EZH2 in cancer. H3K27 methylation is associated with the inhibition of gene expression [59]. In diffuse large B-cell lymphoma, H3K27me1 can be converted to H3K27me2/3, as the substitution of tyrosine 641 (Y641) within the SET domain of EZH2 through heterozygous missense mutations [60]. It has also been shown that EZH2 mutations are a type of loss-of-function mutation in myeloid malignancies [61], 62]. The PRC2 complex regulates H3K27 methylation through its core subunit, EZH2, and can influence chromatin structure [63]. The combination of DZNep and Panobinostat, a pan-histone deacetylase inhibitor, was shown to be stable and effective for AML, follicular lymphomas, and B-cell lymphomas [64]. In diffused large B-cell lymphoma cells, EI1 can inhibit the enzymatic activity of EZH2 through direct binding to enzymes and competition with methyl donor S-adenosylmethionine, which leads to genome-wide H3K27 methylation loss and the activation of PRC2 target genes and can decrease cell proliferation, and arrest the cell cycle and apoptosis through Y641 mutations [65]. The loss of SMARCB1/INI1 expression of the core subunit of the SWI/SNF complex in epithelioid sarcoma (ES) has a great influence on the occurrence of tumors [66]. SWI/SNF, a chromatin remodeler, exerts an opposite effect to that of PRC2 and has been shown to be associated with tumor inhibition [67], 68]. ES also showed an increase in the expression of EZH2. Tazemetostat functions as an inhibitor of EZH2 to inhibit the methylation of H3K27, thereby inhibiting the expression of ES cells [69]. Tazemetostat has been approved for use in patients with advanced epithelioid sarcoma, with phase 2 trials demonstrating antitumor activity and a high safety profile [70].
There are multiple functional domains in Histone demethylase proteins, including binding, recognizing, catalyzing, and interacting with cofactors. For instance, lysine-specific demethylase 1 (LSD1, KDM1A) can demethylate lysine through an amine oxidation reaction and belongs to the first class of demethylases while flavin adenine dinucleotide (FAD) is a cofactor in this process. Recently, it was reported that LSD1 overexpression is necessary for the occurrence and development of AML [71], 72]. The overexpression of LSD1 has been reported in a variety of cancers [72], 73]. As a specific LSD inhibitor, ORY-1001 can inhibit stem cell colony formation, reduce leukemogenesis, and induce the differentiation of AML [74]. It can modulate the Warburg effect by controlling hexokinase 2 (HK2) expression, thereby significantly inhibiting lung cancer cell proliferation, colony formation, and the cell cycle, and inducing apoptosis [75]. It can also play an important role in breast cancer by blocking CSC-driven breast ball formation in breast cancer cell lines that rely on SOX2 expression [76]. Its effective concentration is in sub-nanomolar scale concentrations and shows a time- and dose-dependent manner while being upregulated in H3K4me2 and causing cellular apoptosis in AML [74].
These findings highlight the crucial role of small molecule inhibitors, such as ORY-1001, in targeting specific histone demethylases. By modulating key pathways and gene expressions, these inhibitors offer promising therapeutic strategies for various cancers.
HATs exert an influence on the epigenetic modulation of gene transcription via modifying chromatin histones and can be regulated in cancers and other diseases [23]. HAT1 as an example, has been demonstrated to be associated with upregulated PD-L1 expression in pancreatic cancer [28]. It has been shown that the overexpression of HAT1 can increase the expression of PD-L1 and its knockdown could inhibit the proliferation of pancreatic cancer cells and reduce PD-L1 expression [28]. HAT inhibitors (HATis) can be used as potent blockers of tumorigenesis [77].
HDACis have been well-established as a leading cause of change in the expression of 2–10 % of cellular genes. This can regulate chromatin structure and transcription factors or cofactor binding to promote the acetylation of histones [78]. Vorinostat and Panobinostat are pan-HDACi drugs and have been proven to alter chromatin compaction in the promoter regions of PD-L1 or PD-L2 in TNBC and melanoma [79], 80]. Chromatin compaction can affect the epigenetics of cells, thus becoming a key regulator of silencing genes [81]. HDACis can suppress Tregs and FoxP3 expression, and active NK cells and its ligands, regulate MHC molecules (class I and II) and CD8+ T cell cytotoxicity (Figure 4).
Regulation of histone methylation and acetylation in cancer.
Anticancer drugs targeting the methylation and acetylation of histones
At present, some drugs based on the methylation and acetylation of histones have been developed for the treatment of cancers (Table 1).
Anticancer drugs targeting methylation and acetylation of histone.
| Target | Inhibitor drugs | Function | Reference |
|---|---|---|---|
| H3K79 methyltransferase (DOT1L) | EPZ004777 | Anti-proliferative activities | [35] |
| EPZ567 | |||
| SGC0946 | |||
| Histone lysine demethylase (LSD1) | Trans-cyclopropylamines | Improving inhibitory activity, increasing LSD1 selectivity | [72] |
| GSK2879552 | Inhibiting the proliferation ability of cells | [75] | |
| Histone acetyltransferase (HAT) | HAT Tip60 | Inducing the apoptosis of cells | [25] |
| TH1834 | |||
| Garcinol | |||
| Histone deacetylase (HDAC) | Suberoylanilide hydroxamic acid hydroxamic acid | Affecting cell mitosis and DNA repairing | [27] |
| CG-1521 | |||
| Sodium butyrate | |||
| Entinostat | Enhance the sensitivity of breast cancer to nivolumab and ipilimumab | [82] |
H3K79 methyltransferase (DOT1L)
DOT1L is a key cancer regulator in mixed-lineage leukemia (MLL) rearranged leukemia, and EPZ004777 is its first small molecule inhibitor. Since 2011, numerous studies have reported that EPZ004777 exerts selective anti-cancer activity in MLL. At the same time, other DOT1L inhibitors have been discovered and shown to have a similar effect to that of EPZ004777 [83], [84], [85], [86]. Adenosine or analogous structures appear in all DOT1L inhibitors, as strong protein-protein and protein-DNA interactions between DOT1L and substrate nucleosome, showing comparable competitiveness with the enzyme cofactor, S-adenosylmethionine (SAM). Several research reports have shown that EPZ004777, EPZ5676, and SGC0946 can selectively activate an anti-cancer function in MLL-rearranged leukemia cells. Notably, only after two weeks of treatment, these DOT1L inhibitors can exhibit anti-proliferative activities. In MLL-rearranged leukemia cells, EPZ004777 can selectively target the reduction of the expression of MLL oncogenes to impact the apoptosis and differentiation of cells. Moreover, this also prolongs the survival time in an MV4-11 leukemia mouse model. Another potent DOT1L inhibitor, EPZ5676 has been proven to exert an anti-cancer effect via the regulation of pharmacokinetics. It can cause low oral bioavailability and relatively high clearance in vivo. As a potential drug for the treatment of MLL-rearranged leukemia, EPZ5676 is currently undergoing Phase I clinical trials [87].
LSD1, the inhibitor of histone lysine demethylase
LSD1, a member of the monoamine oxidases (MAO) family, is a histone lysine demethylase [88], 89]. It contains four functional domains, including a SWIRM, an oxidase domain, a putative nuclear localization peptide and a tower domain [90]. In particular, the oxidase domain, the tower domain, and the SWIRM are of great importance for demethylation. The tower domain directly interacts with repressor element-1 silencing transcription factor corepressor 1 to form protein complexes that regulate histone lysine methylation and gene expression. Numerous studies have shown that LSD1 is overexpressed in many types of cancers, including AML, lung, breast, and prostate cancer [91], [92], [93]. A variety of small molecule inhibitors of LSD1, belonging to both reversible and irreversible types have been identified [94], 95]. The main feature of irreversible LSD1 inhibitors is that they can permanently deactivate enzymes by binding to flavin adenine dinucleotide (FAD) [96]. Correspondingly, reversible inhibitors of LSD1 cannot covalently bind to any protein.
The first LSD1 inhibitor was derived from Tranylcypromine, which contains a common cyclopropylamine core structure and can be used as an antidepressant drug. Based on the structure of Tranylcypromine, other LSD1 inhibitors have been developed. A second amine-containing N-substituent is a common feature of highly potent LSD1 inhibitors. For example, the cyclopropylamine moiety on the right side, can not only improve the inhibitory activity but can also increase selectivity for LSD1 to MAO-A and -B [97]. GSK2879552, another potent LSD1 inhibitor, has been reported to inhibit the proliferation ability of small cell lung cancer (SCLC) and AML cells. Moreover, it can also play an anti-cancer role in a SCLC mouse model. Mechanistic studies have shown that GSK2879552 can dysregulate the gene expression of TGF-β in SCLC, and its sensitivity to LSD1 inhibition is correlated with DNA hypomethylation, as shown in a gene set of SCLC cells [98].
The inhibitor of histone acetyltransferase (HATi)
As one of the most common modifications of eukaryotic proteins, acetylation can affect a variety of biological processes, including microtubule function, DNA transcription, protein-protein interactions, and peptide-receptor recognition. HATs and HDACs are well-known regulators of the acetylation status of histones. It has been reported that HATi can reduce acetylation levels of histones and exhibit anti-tumor effects on many cancers [99], 100]. The HATi includes several different structures, such as bisubstrate inhibitors, synthetic compounds, and natural products. In particular, the HAT Tip60 has been identified as a mediator of the response to DNA damage [101]. Its inhibitor, TH1834, can induce the apoptosis of breast cancer cells due to unrepaired DNA damage [102].
The inhibitor of histone deacetylase (HDACi)
HDACs can catalyze deacetylation [103], along with the inhibition of transcriptional processes and the formation of heterochromatin. Currently, HADCs can be divided into four subclasses: class I, class IIa, class IIb, and class III. Class I to III of HDACs are homologous with yeast RPD3, Hda1, and Sir2 family of deacetylases, respectively. HDAC1 to 3 and 8 belong to Class I, while Class II includes two main isoforms: Class IIa (HDAC4, 5, 7, 9) and Class IIb (HDAC 6, 10), with both shuttling between the nucleus and cytoplasm. There are seven types of HDACs in Class III.
This inhibitor of HDACs can block the activity of HDAC by chelating the zinc co-enzyme factor. This results in the hyperacetylation of the lysine residues of the histone. Currently, HDACi can be divided into four groups: short-chain fatty acids, cyclic tetrapeptides, benzamides, and the most common type, hydroxamic acids [104], 105]. An approved drug-targeted hydroxamic acid, suberoylanilide hydroxamic acid has been used in clinical anti-cancer therapy. HDACi is involved in anti-cancer effects in multiple ways, including by affecting cell mitosis, affecting DNA repairing, and improving sensitivity to tumor treatment. For instance, CG-1521 acts as an inhibitor of HDAC to block mitotic spindle formation and impede abscission during the cytokinesis of inflammatory breast cancer. Sodium butyrate, another HDACi, can suppress DNA double-strand break repair, which promotes the cell death of MCF-7 cells [106]. Entinostat, a class I HDACi, has been reported to enhance the sensitivity of breast cancer to lapatinib through FOXO3-mediated Bim1 expression [107]. In addition, HDACi can regulate cell growth and the cell cycle and is involved in DNA repair, indicating that it shows good prospects in cancer therapy (Table 2).
The enzymes of acetylation/deacetylation and methylation and demethylation.
| Type | Regulators/enzymes | Function | Reference |
|---|---|---|---|
| Acetylation | Histone acetyltransferases (HATs) | ||
| GNAT Family (GCN5-related N-acetyltransferases): GCN5 (KAT2A), PCAF (KAT2B) | Involved in transcriptional activation by acetylating histones H3 and H4, which loosens chromatin structure and facilitates transcription factor binding. | [108] | |
| p300/CBP Family: p300 (EP300), CBP (CREBBP) | These have broad transcriptional coactivator functions. They acetylate a wide range of histone (e.g., H3 and H4) and non-histone proteins, regulating processes such as cell cycle progression, DNA repair, and cell differentiation. | [109] | |
| MYST Family: MOZ (KAT6A), MORF (KAT6B), Tip60 (KAT5), HBO1 (KAT7), MOF (KAT8) | Members of this family are involved in various cellular processes, including cell cycle regulation, DNA damage repair, and cell differentiation. For example, Tip60 acetylates H4 and H2AX, playing a crucial role in the DNA damage response. | [110], [111], [112], [113] | |
| HAT1 | The first HAT discovered, primarily acetylates newly synthesized histone H4 in the cytoplasm at lysine 12 (K12). This acetylation is important for the assembly of histone H3-H4 dimers into nucleosomes and chromatin formation. | [114] | |
| Non-histone acetyltransferases | |||
| p300/CBP | While p300 (EP300) and CBP (CREBBP) also acetylate histones, they have broad specificity and can acetylate numerous non-histone proteins, including transcription factors like p53, thereby regulating their activity, DNA-binding affinity, and stability. This acetylation plays a critical role in cell cycle regulation and differentiation. | [115], 116] | |
| PCAF (P300/CBP-Associated Factor) | Similar to p300/CBP, PCAF can acetylate both histone and non-histone proteins, including p53. PCAF is involved in the regulation of transcription, cell cycle progression, and apoptosis through its acetylation targets. | [117], 118] | |
| NATs (N-Acetyltransferases) | This family includes several enzymes that acetylate the N-terminus of proteins, a modification that can affect protein stability, localization, and interaction with other molecules. N-terminal acetylation is a common modification that affects a significant portion of the eukaryotic proteome. | ||
| MYST Family | Although known for their roles in histone acetylation, members of the MYST family, such as MOF (KAT8), also target non-histone proteins. For example, MOF can acetylate p53 and is involved in DNA damage response and maintenance of stem cell identity. | [119], 120] | |
| GCN5 (General Control Non-derepressible 5) | Besides histones, GCN5 (KAT2A) acetylates non-histone proteins involved in transcription regulation, such as TFIID, thus influencing transcription initiation and gene expression. | [121] | |
| Deacetylation | Histone deacetylases (HDACs) | ||
| Class I HDACs: HDAC1, HDAC2, HDAC3, and HDAC8 | They are involved in the regulation of gene expression and are crucial for cell cycle progression and differentiation. | [122], [123], [124], [125] | |
| Class II HDACs: Subdivided into Class IIa (HDAC4, HDAC5, HDAC7, HDAC9) and Class IIb (HDAC6, HDAC10) | Class IIa HDACs are involved in tissue-specific gene expression and developmental processes. Class IIb HDACs, particularly HDAC6, have a unique role in cytoplasmic structures and are involved in the regulation of cell motility, autophagy, and stress response. | [126], [127], [128], [129] | |
| Class III HDACs (Sirtuins): SIRT1-SIRT7 | Sirtuins are involved in the regulation of metabolism, stress responses, and longevity. They require NAD+ for their deacetylase activity, linking their activity to the cellular metabolic state. | [130], [131], [132], [133] | |
| Class IV HDAC: HDAC11 | HDAC11 has been implicated in both gene repression and activation, but its specific roles are less well understood compared to other classes. | [134] | |
| Methylation | DNA Methyltransferases (DNMTs) | ||
| DNMT1 | Maintains methylation patterns after DNA replication by copying methylation marks from the parent strand to the daughter strand, ensuring the heritability of epigenetic information. | [135] | |
| DNMT3A and DNMT3B | Responsible for de novo methylation, establishing new DNA methylation patterns during development and in differentiated tissues. | [136], 137] | |
| DNMT3L | Lacks enzymatic activity but is crucial for the establishment of maternal genomic imprints; acts as a stimulatory factor for DNMT3A and DNMT3B. | [136] | |
| Histone Methyltransferases (HMTs) | |||
| EZH2 (Enhancer of Zeste Homolog 2) | Part of the polycomb repressive complex 2 (PRC2), which trimethylates histone H3 on lysine 27 (H3K27me3), leads to transcriptional repression of target genes. | [138] | |
| SUV39H1 (Suppressor of Variegation 3-9 Homolog 1) | Methylates histone H3 on lysine 9 (H3K9me3), a mark associated with heterochromatin formation and gene silencing. | [139] | |
| DOT1L (Disruptor of Telomeric Silencing 1-Like) | The only known enzyme that methylates histone H3 on lysine 79 (H3K79), is involved in transcriptional activation and repression, as well as DNA damage response. | [140] | |
| RNA Methyltransferases | |||
| METTL3 | The main catalytic component of the m6A methyltransferase complex, responsible for the N6-methyladenosine (m6A) modification on RNA, which affects RNA stability, translation efficiency, and splicing. | [141] | |
| METTL14 | Works closely with METTL3 as part of the m6A methyltransferase complex, contributing to the recognition of RNA substrates but with limited catalytic activity on its own. | [142] | |
| WTAP (Wilms Tumor 1 Associated Protein) | Although not a methyltransferase itself, WTAP is an essential regulatory subunit of the m6A methyltransferase complex, influencing the localization and substrate specificity of the complex. | [143] | |
| METTL16 | Methylates the U6 small nuclear RNA (snRNA) and a subset of mRNAs, playing roles in splicing regulation and other RNA processing events. | [144] | |
| KIAA1429 (VIRMA, Virus-Responsive Molecule A) | KIAA1429 is vital for directing the m6A methyltransferase complex to specific RNA regions, especially around the stop codon and the 3′ untranslated regions (3′UTRs), thereby influencing the m6A modification landscape on mRNA. This modification impacts mRNA stability, translation, and nuclear export. | [145] | |
| RBM15 (RNA binding motif protein 15) | RBM15 acts as an adaptor protein within the m6A methyltransferase complex, guiding the complex to RNA substrates for methylation. It is involved in RNA processing events like alternative splicing and plays a role in X chromosome inactivation. | [146] | |
| ZC3H13 (Zinc Finger CCCH-Type Containing 13) | ZC3H13 is crucial for anchoring the m6A methyltransferase complex within the nucleus, facilitating the methylation of nuclear RNAs. It plays a significant role in RNA processing and export, impacting gene expression regulation. | [147] | |
| Demethylation | Histone Demethylases | ||
| LSD1 (Lysine-Specific Demethylase 1) | Demethylates mono- and dimethylated lysine 4 of histone H3 (H3K4me1/2), usually leading to transcriptional repression. | [148] | |
| JHDMs (Jumonji C-Domain-Containing Histone Demethylases) | A large family of enzymes that can remove methyl groups from various lysine residues on histones, including H3K9, H3K27, H3K36, and H4K20, thereby regulating gene expression positively or negatively depending on the specific lysine residue demethylated. | [149] | |
| DNA Demethylases | |||
| TET Enzymes (Ten-Eleven Translocation) | Convert 5-methylcytosine (m5C) to 5-hydroxymethylcytosine (5hmC) and further oxidation products, facilitating DNA demethylation. This process is important for active DNA demethylation, embryonic development, and cellular differentiation. | [150] | |
| RNA Demethylases | |||
| FTO (Fat Mass and Obesity-Associated Protein) | The first identified m6A demethylase, capable of removing m6A modifications from RNA, thereby influencing RNA metabolism and processing, including mRNA stability and splicing. | [151] | |
| ALKBH5 (AlkB Homolog 5) | Another m6A demethylase that specifically demethylates m6A in mRNA and non-coding RNA, affecting RNA metabolism, export, and decay, as well as the regulation of gene expression and cellular stress response. | [152] | |
| NSUN2 (NOP2/Sun RNA Methyltransferase Family, Member 2) | Catalyzes the formation of m5C in various RNAs, including tRNAs, mRNAs, and non-coding RNAs, affecting RNA stability and translation. | [153], 154] | |
| TRMT6/61A (TRNA Methyltransferase 6/61A) | Responsible for the N1-methyladenosine (m1A) modification in tRNAs, influencing tRNA stability and the efficiency of protein synthesis. | [155] | |
The dilemma of research on drug targeting histone methylation or acetylation
Although the inhibition of histone methylation or acetylation has been shown to be promising for cancer treatment, the efficacy of some inhibitors needs to be enhanced. Owing to the reversible nature of epigenetic modifications, certain inhibitors need to be taken continuously to achieve maximal antitumor effects and clinical response. There are many factors that adversely affect the bioavailability and antitumor activity of the inhibitors, including rapid metabolism, a high degree of protein binding, rapid inactivation of reactive functional groups, and rapid clearance. For instance, it has been reported that butyrate and phenylbutyrate are rapidly degraded after intravenous administration, indicating that continuous venous transfusion for 120 days at a dose of ≥400 mg/kg/day is needed for some clinical trials [156]. Chemical modifications may be a good method to increase efficacy. For instance, the natural inhibitor, S-adenosylhomocysteine (SAH), exhibits inhibitory activity against DOT1L with a Ki value of 260 nM. A valid methodology for inhibiting the activity of DOT1L is by replacing the sidechain in SAH with a tert-butylphenyl urea containing a tertiary amine group. The Ki value, 0.3 nM, is about 860-fold higher than the activity of SAH. However, since the proteins that control histone methylation or acetylation are relatively homologous with each other, most cofactors used in this process are the same, and problems have been encountered with the discovery of more highly selective small molecule inhibitors. Currently, research on potent inhibitors has often ended in failure in clinical trials and the cost is high. Therefore, high-throughput screening, as well as the designing and synthesis of inhibitors need to be performed.
It is necessary to know the association between cancer therapy targets and histone modifying enzymes before designing and synthesizing inhibitors. Genetic screening of gene mutations may offer a valuable method of identifying potential targets in clinical tissues. The clinical correlation and mechanisms by which mutation functions to exert pathogenesis also require profound studies. Epigenetic therapies lack specificity; some inhibitors have low efficacy when used alone. HDACi has already been used in combination with immunotherapy, showing slower tumor growth in combination with the HDACi, Panobinostat, and anti-PD-1 antibody therapy. This novel approach to cancer needs more trials to be conducted.
Therefore, we should pay close attention to the underlying potential toxic effects caused by the inhibition of histone methylation or acetylation enzymes, since these two modifications also appear in normal physiology. For instance, an inhibitor of LSD1 could play an anti-cancer function in MLL-AF9 transformed leukemic stem cells by decreasing leukemia-relevant gene expression [157]. However, in an MLL-AF9 leukemia mouse model, this inhibitor showed severe systemic toxicities with unclear mechanisms. Therefore, toxicological studies need to be conducted to confirm this result.
Conclusions
In recent years, the role and regulation of histone methylation and acetylation in cancer and the mechanism of drug action have been thoroughly discussed. Along with advancements in research, targeted modification enzyme inhibitors have become a hot research focus in cancer therapy. Research on epigenetic-targeted drugs is still in its infancy. Many efforts are needed in the fields of dominant biology, structural biology, and pharmacodynamics. Clinically unmanageable toxicities should not be ignored. To accelerate the development of epigenetic drugs, epigenetic chemical probes, assays, antibodies, and X-ray crystal structures have been connected, and is known as the Structural Genomics Consortium (SGC). SGC provides a resource-sharing platform for the application of 3D protein structures to genomics and advancements of the discovery of small-molecule targeted drugs [158]. Moreover, the sequencing of patients with tumors can help to identify epigenetic targets and determine sensitivities to therapeutic interventions. Overall, these studies can help us understand the role of histone modifications and related enzymes in cancer initiation and progression, and provide a theoretical basis that can be used to enhance cancer treatment.
Funding source: Project of High-Level Talents in AHUTCM
Award Identifier / Grant number: 2019rcZD001
Funding source: Key Project of Anhui Provincial Department of Education
Award Identifier / Grant number: 2023AH050870
Funding source: Scientific research project of Anhui University of Traditional Chinese Medicine
Award Identifier / Grant number: 2022AH050415
Funding source: Horizontal scientific research Project
Award Identifier / Grant number: 2021HZ002 and 2022HZ009
Funding source: Clinical science research project of the First Affiliated Hospital of Anhui University of Chinese Medicine
Award Identifier / Grant number: 2020yfyzc06
Acknowledgments
We thank all authors prepared, written, reviewed and edited the entire manuscript.
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Research ethics: Not applicable.
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Informed consent: Not applicable.
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Author contributions: Su Bu and Ting Ye wrote the paper; Hang Gao retrieved documents and designed illustrations; Hang Song and Yong-fu Zhu conceived and designed the article. All authors have read and approved the manuscript.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: We have no conflict of interest to declare.
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Research funding: This research was funded by Project of High-Level Talents in AHUTCM [2019rcZD001]; Clinical science research project of the First Affiliated Hospital of Anhui University of Chinese Medicine [2020yfyzc06]; Scientific research project of Anhui University of Traditional Chinese Medicine [2022AH050415]; Horizontal scientific research Project [2021HZ002 and 2022HZ009] and Key Project of Anhui Provincial Department of Education [2023AH050870].
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Data availability: Not applicable.
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Artikel in diesem Heft
- Frontmatter
- Editorial
- The essential development of integrative oncology
- Review Articles
- Novel post-translational modifications in cancer
- The assessment of 5-aminolevulinic acid photodynamic therapy in glioblastomas
- Histone methylation and acetylation in cancer: mechanism, progression, and targets
- Current advancements in PD-L1 modulation by CMTM6 in malignant tumors
- Research Articles
- Combination of oxabicycloheptene sulfonate (OBHS) and antidiabetic drugs synergistically inhibits proliferation in human breast cancer cells
- Cell indices as predictors of progression-free survival in multiple myeloma: a retrospective cohort study
- The Y44 residue point mutation in CXCL14 reveals the significance of CXCL14 protein stability in anti-tumor activity
- Oxeiptosis gene expression profiling identified TCN1 as a prognostic factor for breast cancer
- Integrated analyses reveal prognostic markers associated with cancer-associated fibroblasts in oral squamous cell carcinoma
- The roles of G protein-coupled receptor genes and the tumor microenvironment in esophageal squamous cell carcinoma
- Combining the Albumin-to-fibrinogen ratio and pathologic factors predicts survival in surgically treated patients with esophageal squamous cell carcinoma
- Joint multi-omics screening of neutrophil-related biomarkers for lung adenocarcinoma
- High-throughput sequencing reveals twelve cell death pattern prognostic target genes as potential drug-response-associated genes in the treatment of colorectal cancer cells with palmatine hydrochloride
- Article Commentary
- A commentary: optimizing the prevention of osteoradionecrosis in head and neck cancer treatment
Artikel in diesem Heft
- Frontmatter
- Editorial
- The essential development of integrative oncology
- Review Articles
- Novel post-translational modifications in cancer
- The assessment of 5-aminolevulinic acid photodynamic therapy in glioblastomas
- Histone methylation and acetylation in cancer: mechanism, progression, and targets
- Current advancements in PD-L1 modulation by CMTM6 in malignant tumors
- Research Articles
- Combination of oxabicycloheptene sulfonate (OBHS) and antidiabetic drugs synergistically inhibits proliferation in human breast cancer cells
- Cell indices as predictors of progression-free survival in multiple myeloma: a retrospective cohort study
- The Y44 residue point mutation in CXCL14 reveals the significance of CXCL14 protein stability in anti-tumor activity
- Oxeiptosis gene expression profiling identified TCN1 as a prognostic factor for breast cancer
- Integrated analyses reveal prognostic markers associated with cancer-associated fibroblasts in oral squamous cell carcinoma
- The roles of G protein-coupled receptor genes and the tumor microenvironment in esophageal squamous cell carcinoma
- Combining the Albumin-to-fibrinogen ratio and pathologic factors predicts survival in surgically treated patients with esophageal squamous cell carcinoma
- Joint multi-omics screening of neutrophil-related biomarkers for lung adenocarcinoma
- High-throughput sequencing reveals twelve cell death pattern prognostic target genes as potential drug-response-associated genes in the treatment of colorectal cancer cells with palmatine hydrochloride
- Article Commentary
- A commentary: optimizing the prevention of osteoradionecrosis in head and neck cancer treatment
