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Scientists have made a remarkable breakthrough by uncovering DNA and its role in living organisms. Epigenetics examines the phenotypic divergences due to DNA methylation and its effects at certain genetic spots. Epigenetic and genetic problems combine to cause cancer and its growth, as seen by frequent mutations in genes that manage the epigenome. Recently, new therapies targeting epigenetic alterations have been proposed. Drugs with longer shelf life and better absorption are also being manufactured and tested. On this aspect, CRISPR technology has been used to create various strategies for epigenetic engineering and is a practical approach to understanding and manipulating biological processes. Furthermore, studies on the advantages of probiotics have advanced previous interventional studies to recognize the molecular mechanisms involved. Numerous probiotic genomes include epigenetic components that influence gene expression for fundamental functions. Consequently, we suggest investigations incorporating genomic and meta-epigenomic information to better understand the mode of action of probiotics and their related microbiomes in epigenetic therapy. Here, we review established epigenetic discoveries, combined with the rapid advancement of immunotherapies, to create new possibilities for cancer treatment.
Centre for Neuroscience, Indian Institute of Science, Bangalore, Karnataka, India
Shobha Rani Papanna
Genespy Research Services Private Limited, Mysuru, Karnataka, India
Sundru Manjulata Devi*
SVR BioScience Research Services, Mysuru, Karnataka, India
*Address all correspondence to: svrbioscience@gmail.com;, manjusundru@gmail.com
1. Introduction
One of the greatest discoveries made in the twentieth century is recognizing that phenotypic changes are not merely based on genetic alterations but are implications due to external stimuli/epigenetic factors [1]. Epigenetic trait is a phenotype whose inheritance is stably heritable without altering the genetic code. Thus, for the normal development of an organism, regulations in the epigenome or epigenetic state are equally important as changes in gene expression. Today, epigenetics is a dynamic field aimed at studying individual and fundamental processes in mitosis and meiosis [2]. Several endogenous factors are found to be involved in modulating epigenetic states and their activity can be affected by each other. Cellular functions can be preserved for an extended period by generating and transmitting epigenetic states [2]. Genomic characteristics such as chromatin reconstitution and epigenetic factors’ alterations could play a role in epigenetic states. However, epigenetic changes must be precisely defined to obtain a complete and detailed picture [3, 4, 5]. Understanding the role of epigenetic alterations and their effect on gene expression and the awareness that epigenetic traits are reversible has opened the door to developing diagnostic tools to treat several diseases, including cancers [6].
Epigenetic alterations are essential for the regulatory processes associated with several biological phenomena, including genomic imprinting, X-chromosome inactivation, control of tissue-specific gene expression, genomic stability, repression of transposable elements, aging, and some diseases, including cancer [7]. The most common epigenetic modifications that modify DNA accessibility to transcriptional machinery and impact gene expression are acetylation, methylation, phosphorylation, biotinylation, and RNA interference [8]. Roberti et al. [9] have identified three main components of the epigenetic system: DNA methylation, post-translational histone modifications, and noncoding RNAs (ncRNAs). The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)system (CRISPR-cas9) is a naturally occurring defense system in many bacteria and archaea to protect from invading viruses or plasmids [10]. CRISPR system with the capacity to program Cas9 has revolutionized medical research, biotechnology and agriculture. It is a precise genome editing tool that can modify specific genome regions in eukaryotic cells, particularly mammalian cells [11]. Cas proteins are endonucleases that sever the target nucleic acid sequence. Mutations in genes that encode Cas proteins can generate deactivated cas (dCas) proteins that maintain their ability to bind DNA in a manner targeted by gRNA and serve as programmable DNA binding domains [12]. CRISPRi/a domain proteins can be used in epigenetic studies to alter histone acetylation and methylation [13]. The dCas-based demethylation approach was discovered to improve cell disease conditions. Scientists have found that countering epigenetic changes can be an effective cancer therapy [7, 14].
The trillions of intestinal microflora have an intimate relationship with the host and impact the host’s physiology and pathology. They play a role in food fermentation, vitamin synthesis, and maintaining intestinal epithelial function. The microbiome affects the host’s epigenetics, immune system, and metabolism. Certain epigenetic changes after exposure to bacteria suggest a connection between the microbiome and the epigenome [15]. Investigating the epigenetics and para-epigenetics of a probiotic organism and its microbiome is a difficult but critical step in understanding the probiotic mechanism [1]. Researchers have used CRISPR-Cas to precisely alter probiotic organisms, explore epigenetics, and improve the effects of probiotics [16, 17]. Certain epigenetic changes during childhood are essential for adult health, and short-chain fatty acids (SCFAs), such as butyrate, can influence human genes by being epigenetic regulators [18, 19]. Researching the various probiotic molecules and their interactions with human epigenetic systems could reveal new health benefits and assess the safety of consuming these organisms. Current and future technologies can help researchers understand microbial meta-epigenomics and how it can improve human health. In the current study, a search strategy was assigned, and the search words with “EPIGENETICS”, CRISPR-cas9 EDITING IN EPIGENETIS” and PROBIOTICS THERAPY IN EPIGENETICS” has been used and the related articles were retrieved from PubMed, Web of Science, and Scopus databases from 2010 to Jan 2023. This article discusses epigenetic therapy and its potential new methodologies using the CRIPSR-cas system, epigenetic drugs, and epigenetic regulation by probiotic bacteria and the gut microbiota.
2. The emergence of the CRISPR Cas9 system in epigenome editing
Epigenetic changes at the target site can be achieved by securing the epigenetic effectors to sequence-specific DNA-binding domains (DBDs). Although the discovery of zinc fingers (ZFNs) and TALENs succeeded in DNA binding and genome editing efficacy, targeting different regions required redesigning and reengineering of these proteins. This has prevented the scientific community from using ZFN and TALEN effectively [20]. The rise of the CRISPR Cas system has trounced this major hurdle. Although the Cas9 protein of the type II Streptococcus pyogenes system is the most widely used in the CRISPR Cas system in gene knockout, the CRISPR-Cas system in its basic form has become a powerful technology to flexibly target any specific site in the genome simply by employing small guide RNAs (sgRNA). Because most Cas proteins are nucleases, mutations in Cas-encoding genes convert them to deactivated Cas (dCas) proteins, inhibiting their nuclease activity while retaining DNA binding capability. Thus, dCas proteins have become programmable DBP, and the ability to bind dCas9 to specific DNA loci can be altered using sgRNA (Figure 1) [12].
Figure 1.
Strategies for gene activation and repression using the CRISPR Cas9 system. (A) Targeting specific DNA sequence for activation or repression through (a) direct binding of effector domain (ED) to dCas9; (b) effector domains bound to the sgRNA scaffold named srRNA 2.0; and (c) recruitment of the effector domain to the target site by the Sun tag system. (B) The concept of gene inactivation through CRISPR interference (CRISPRi) using KRAB bound to dCas9.
2.1 CRISPR Cas9 in epigenome activation and repression
Soon after discovering that wild-type Cas9 could be used as a programmable endonuclease, researchers began to exploit dCas9 for gene regulation studies. For epigenome editing through CRISPR Cas9, the setup consists of a toolbox for expressing sgRNA. In these dCas9 and effector domains, the activation domains retain their function when fused to other proteins with different DNA binding moieties [21]. Several activation domains have met this criterion which includes the 16-virion protein (VP16) of the herpes simplex virus type I, the VP64 domain is a tetramer of the minimal activator VP16, p65, the largest subunit of the NF-kappa B transcription factor, the Rta domain encoded by Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8, human heat shock factor 1 (HSF1) etc. [21]. The CRISPR activation cabinet (CRISPRa) consisting of dCas9 fused to the activation domain in various combinations has been used in the transcriptional activation of genes. In vitro studies showed that the dCas9-VP64 and dCas9-p65 fusion proteins have activated the target reporter gene in the HEK293 reporter cell line [22]. However, the VPR tripartite activation domain designed and characterized by George et al. reported a robust multi-locus activation, outpacing VP64 alone. Furthermore, for nuclease and activation pursuit using the dCas9-VPR system, maximum efficiency was achieved by changing the length of the gRNAs [23].
2.1.1 Increment in the transactivation potential using dCas9
Several interesting CRISPRa studies have described successful gene activation using dCas9-based tools and increased transcriptional activation with multiple targeting of sgRNA. However, Konermann et al. [24] have introduced the concept of increased activation using single sgRNA and modification of the gRNA scaffold and have named it sgRNA2.0. The main objective was to create a flexible sgRNA capable of grafting additional activation domains to the target site dCas9. Enhanced stimulation can be achieved with a single sgRNA through multiple activation domains. A similar concept of activation domain recruitment to the target site was developed by Tanenbaum et al. [25] and named the Sun tag system. This approach uses a recombinant peptide array (SunTag) that recruits multiple antibody fusion proteins (activator domains). This system achieved higher levels of transcription activation with recruitment of VP64 to dCas9 through Suntag to activate the CXCR4 gene in K562 cell lines using a single sgRNA. It achieved 25 times higher transcription levels than conventional dCas9-VP64-mediated activation [25]. In addition to the techniques manipulated by dCas9 to increase gene expression activation, light-controlled manipulation of epigenetic and endogenous genes was introduced [24, 26, 27]. The principle involved in this mode of gene manipulation is that two interaction partners dimerize upon blue-light activation, where one partner is fused to a DNA-binding protein and the other to the transcriptional activation domain. Recently, optogenetic systems have used dCas9 and photoinducible dimerization for precise modulation of gene expression of mammalian cells.
2.1.2 dCas9-mediated transcriptional repression
Qi et al. initially developed the concept of CRISPR interference (CRISPRi) [12], where dCas9 and sg RNAs target a specific transcriptional start site and interfere with the activity of DNA binding proteins such as Polymerase II. With this development of CRISPRi, modifications have been made in which a stronger repressor complex, such as Kruppel’s associated Box (KRAB), was fused to dCas9, resulting in a stronger and more specific gene repressor than dCas9 alone [22]. KRAB has a highly conserved amino-terminal region of many Krüppel-class Cys2His2 zinc finger proteins with repressive function [28]. The KRAB domain functions with the KAP1 corepressor that recruits heterochromatin protein 1 (HP1), which recognizes and binds methylated H3K9, obtained by methyltransferase activity and recruits more HMTs, resulting in chromatin condensation of neighboring nucleosomes [29]. Several success stories reported the use of dCas9-KRAB fusion in gene repression, and this fusion system can successfully recruit chromatin-modifying complexes for amplified CRISPRi effects [21].
2.2 Epigenome editing through chromatin modulation using CRISPR Cas9
Genomic DNA is organized on a nucleosomal scale by wrapping around various histones that can be modified post-translationally using chemical moieties and/or by chemical modification, such as methylation at 5-carbon in cysteine residues (5-mC), which are collectively termed chromatin markers [2]. Gene editing through chromatin edits has become an important aspect in the epigenetic field in altering gene expression. dCas9 has been deployed to modulate various histone proteins within a specific DNA region that affects gene expression [2]. Although gene expression levels through chromatin modulation are modest compared to CRISPRi/a technologies, the highest levels of expression are achieved by H3K27ac deposition or DNA demethylation [30, 31].
2.2.1 dCas9 in methylation and demethylation of chromatin marks
Since aberrant methylation has several pathological implications, especially in several cancers, there is an urgent need to manipulate these epigenetic characteristics. Although small molecules such as 5-azacytidine that target DNA methylation as epigenetic inhibitors are in clinical use, these inhibitors target the entire genome where normal methylation occurs [20]. This limitation has been overcome by targeting specific gene loci mediated by the dCas9 system, which has been used to deposit and remove methylation from target genome sites. The deposition of DNA methylation has been achieved by fusion of dCas9 with the catalytic domain of eukaryotic DNA methyl transferase (DNMT3A) [32, 33] or prokaryotic DNA methyltransferase (MQ3) [34]. In addition to targeted DNA methylation, the active removal of methylation marks from the endogenous DNA sequence is another mode of gene expression manipulation. Ten–eleven translocation (TET) proteins (TET1, TET2 and TET3) are involved in endogenous DNA demethylation that regulates cell type-specific gene expression. Therefore, in epigenetic DNA demethylation using the CRISPR system, guidable dCas9 fused to TET-1 has been used to achieve locus-specific DNA demethylation [31, 35, 36, 37].
2.2.2 dCas9 mediated modification of histone proteins
In addition to the role of methylation and demethylation in gene regulation, epigenetic information is stored in histone proteins that wrap DNA around them to form chromatin fiber. These epigenetic features in a cell are constituted by post-translational modification of the histone tails that reveal key insights into regulatory activity. For example, mono and dimethylation at the four positions of lysine of Histone H3 (H3K4me1/2) and acetylation at the 27 positions of acetylation of Lysine (H3K27ac) are elements of active distal regulation. At the same time, trimethylation (H3K4me3) is a marker of active or poised bivalent promoters [11]. Since specific writers, correctors, and erasers regulate the modification of chromatin, researchers have used the dCas9 system to recruit histone modifiers for the methylation and demethylation of histone proteins [20]. Examples of histone-targeted epigenome editing include LSD1, a histone demethylase that removes the H3K4me2 mark, which was fused to dCas9, resulting in a substantial local decrease in the active enhancer markers H3K4me2 and H3K27ac and altered expression of target genes [38]. Unlike these findings, a fusion of histone acetyltransferase P300 with dCas9 resulted in a significant increase in local induction of H3K27ac expression in both the promoter and enhancer regions [39]. Histone modifications through the CRISPR system were used to suppress gene activity where local induction of H3K4me3, a marker of the active promoter for the re-expression of silenced targets, was used. Histone deacetylation by fusion of full-length histone deacetylases (HDAC) with dCas9 was shown to reduce H3k27ac and ultimately down-regulate target gene expression [40].
3. Gut microbiota and probiotics: the mysterious players in epigenetic changes
The gut microbiota/microbiome is the collective term used for the genes contributed collectively by viruses, bacteria, and fungi that are present in different regions of the human body and play a dynamic role in the health of the individual human [41]. Human gut co-habitants with various symbiotic microorganisms, including Bacteroides, Firmicutes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia. The number and composition of these microbial species can vary according to age, diet, and lifestyle [42, 43]. The gut microbiota colonizes from the time of delivery and during breast feeding that gets continuously modulated during development due to dietary and environmental factors [44].
Food and Drug Administration (FDA) and World Health Organization (WHO) define probiotics as “live microorganisms that can provide health benefits to the host when administered in adequate amounts” [45]. Well-established probiotic bacteria includeLactobacillus rhamnosus, Lactobacillus reuteri, Bifidobacteria, Lactobacillus casei, Lactobacillus acidophilus, Bacillus coagulans, Escherichia coli strain Nissle 1917, and Enterococcus faecium SF68 [46]. In addition to protecting the intestinal tract, probiotics help improve various diseases, including cardiovascular disease, diabetes, and obesity [10, 47]. The well-known fact is that probiotics that restore intestinal microbiota balance support their efficiency in preventing the development of chronic immune-mediated diseases (Figure 2).
Figure 2.
A schematic representation of the external factors responsible for inflamed gut and the altered phenotype due to epigenetic modifications. The figure also depicts epigenetic therapy and the restoration of a healthy gut by epigenetic drugs, probiotics, and their metabolites.
As there was substantial evidence that the intestinal microbiota and probiotics impact several metabolic functions within the human body, such as digestion, absorption of nutrition, regulation of hormonal secretion, modulation of inflammation and immunity processes, synthesis of vitamins and various metabolites, dysbiosis of this microbiota negatively influences the onset of diseases such as obesity, diabetes, inflammatory bowel disease, cancer, etc. [44, 48, 49]. In recent years, the commensal microbiota has also been appreciated to play a prominent role in host epigenetics by altering gene expression, affecting homeostasis and health status [44, 50, 51]. Although the mechanism through which the gut microbiota regulates host epigenetic changes remains a mystery, this has, however, been revealed through studies with advanced computational tools for metagenomics that have focused on understanding the crosstalk between the microbiota and epigenetics [52].
3.1 Gut microbiota and host epigenetic features
Host epigenetics can influence the shaping of the microbiota in the intestine. Studies have shown that host miRNAs could control microbial gene transcription, thus modeling the structure of the microbial community, vice versa was observed where the gut microbiota and its metabolites were found to regulate epigenetic changes and influence host metabolism [41]. Short-chain fatty acids (SCFAs) are the main metabolites in host epigenome modulation that are produced by intestinal microbes and are found to affect body health and disease status [53, 54]. The gut microbiota synthesizes many bioactive compounds that serve as epigenetic substrates, cofactors, or regulators of epigenetic enzyme activity [55, 56]. For example, folate and B vitamins (B2, B12) donate methyl groups for DNA or histone methylation. SCFAs inhibit the deacetylase activity of histone deacetylases (HDACs), leading to changes in chromatin [57, 58]. Studies in rodent models have shown that the gut microbiota was found to influence host epigenetic transcriptome markers. Alteration of intestinal microflora in normal, modified, and germ-free (GF) mice was found to affect the modification of N6-methyladenosine (m6A) in the cecum and the decrease in expression in the liver, which ultimately affected host metabolism, inflammation, and antibacterial process. Akkermansia muciniphila and Lactobacillus plantarum could influence the modification of m6A in mono-associated mice [59]. This microbiota was also found to modulate host miRNA expression patterns to maintain intestinal homeostasis [60]. The intestinal microflora negatively regulates miR-107 expression in dendritic cells and macrophages, thus affecting the activity of the MyD88 and NF-B pathways, which subsequently influenced immune homeostasis and the expression of the target gene IL-23p19, which are responsible for oral cancer [61]. Probiotic supplementation could prevent and treat colon cancer by regulating miRNAs [6]. Coculture of probiotic Leuconostoc mesenteroides with HT-29 demonstrated effective down-regulation of miRNA-21 and miRNA-200b, thus promoting colon cancer cell apoptosis [62].
3.2 Probiotic and host epigenetics
Probiotics reduce the risk of certain diseases primarily through clinically validated mechanisms involving epigenetic regulation. The intestinal flora in the large intestine undergoes fermentation to transform dietary fiber into SCFAs, with butyrate being one of the major SCFAs produced [41]. SCFAs such as acetate, propionate, and butyrate are found to modulate the host’s immune system [63]. Gut bacteria and some probiotics produce enzymes such as methyltransferases, acetyltransferases, deacetylases, Bir A ligase, phosphotransferases, kinases, and synthetases. Furthermore, they produce S-adenosylmethionine (SAM), acetyl-CoA, NAD+, α-KG, and ATP, which are essential cofactors for many epigenetic processes that regulate DNA methylation, post-translational histone modifications, and nucleosome position [41, 44, 51]. Butyrate is an anti-inflammatory molecule produced by the gut microbiota and some probiotics can influence the host’s epigenome by decreasing intestinal permeability, preventing autoimmunity for type 1 diabetes (T1D), and protecting against autoimmunity of islets [64, 65].
SCFAs are the main probiotic metabolites that have been indicated to have a protective function in the intestine and exert anti-inflammatory effects in several animal and human models. SCFAs exert health-promoting actions by lowering intestinal pH, acting as energy sources for colon-inhabiting microbes, stimulating colonic blood flow, helping in the contraction of smooth muscle cells, enhancing transepithelial chloride secretion, and aiding in the proliferation of colonic epithelial cells. These SCFAs are the class of epigenetic drugs with histone deacetylase inhibitory activity (HDACi) that plays a vital role as anticancer agents with strong antiproliferative effects on tumor cells [66, 67]. The administration of SCFAs, such as butyrate and acetate, has shown promising results in ameliorating inflammatory lesions in mouse models of allergic airway disease and colitis [68]. The probiotic bacterium Propionibacterium freudenreichii produced a high level of SCFA, acetate, and propionate [69]. Butyrate, acetate, polyphenols, and vitamins are the main metabolites of intestinal microbes that participate in epigenetic processes. Table 1 lists some examples of probiotic bacteria that modulate the epigenetic makeup with their functional attributes. Studies have shown that butyrate can reduce inflammation (by increasing IL-10 expression) in inflammatory bowel disease and help protect against colitis and mortality [81]. Another LMW associated with epigenetic regulation is acetate, which is one of the immunomodulatory peptide drugs, “Glatiramer Acetate”. This was reported to increase the expression of the FOXP3 transcription factor (Forkhead box P3), which increased Treg cell proliferation and differentiation. This reduced the rate of diabetes and insulitis in NOD mice [82]. These SCFAs inhibit HDAC activity, protect against neurodegenerative diseases, and promote immunoglobulin secretion and intestinal mucosal barrier function [83]. Vitamins such as B2, B12, and B6 are essential for an enzyme that systemizes SA, the primary methyl-donating substrate for DNMT and HHMT. Probiotic species such as Lactobacillus and Bifidobacterium can confer better protective effects by biotinylating proteins in the intestines. This process is important for DNA repair and chromatin structure [84].
Bacteria
Epigenetic Changes
Health effect
Reference
Lactobacilli
Down-regulated miRNAs (miR-200b, miR-215, and miR-192)
Maintain homeostasis and shape the host response to infection
VSL#3 (VSL Pharmaceuticals, Ft Lauderdale, FL, USA): 3 × 1011 CFU/g of bifidobacteria (B. longum, B. infantis, and B. breve), lactobacilli (L. acidophilus, L. casei, L. delbrueckii subsp. L. bulgaricus and L. plantarum) and Streptococcus salivarius subsp. thermophilus.
Increases IL-10 production from Peyer patches and the spleen, along with increased expression of IL-10 in the pancreas.
Prevent the development of autoimmune diabetes in NOD mice and Induced immunomodulation by a reduction in insulitis severity
Reduces the expression of insulin receptor substrate 1, protein kinase B (Akt / PBB), IKKa and IkBa, protein-1 (MCP-1) and interleukin-6, (IL-6)
Promotes recovery of β-cells of pancreas cell-cells and increases insulin sensitivity in mice by enhancing the function of the insulin signaling pathway as a promising strategy for the treatment of diabetes.
Epigenetic therapies are a promising new area of treatment for cancer and other diseases. They involve manipulating gene expression using drugs, probiotic bacteria, enzymes, or other molecules that interact with DNA. The gut microbiota and probiotics can affect the host epigenome by activating epigenetically silenced genes in cancer cells. Butyrate, produced by gut microbiota can prevent colon cancer and other diseases by reducing pro-angiogenic factors such as EGF and HIF 1α [85]. Sodium butyrate is an HDAC inhibitor and can increase cell death in human medulloblastoma cells [86]. Below we have discussed the epigenetic treatment for major organs that are effected by cancer, including lung, liver, gastric colon, breast, etc.
4.1 Epigenetic therapy in gastric cancer (GC)
GC is one of the most fatal forms of cancer in the world. Its grim prognosis is due to the complexity of the disease, late diagnosis, and unsatisfactory treatments. In addition to genetic changes and external influences, studies have shown that modifications in epigenetic processes are instrumental in the emergence and development of gastric tumors, which has become a distinctive feature of GC [87]. In most cases, it is caused by Helicobacter pylori infection characterized by chronic gastritis and peptic ulcers. H. pylori harboring the pathogenicity island of the cytotoxins-associated gene (CagPAI) induces the dephosphorylation of histone H3S10, H3 threonine 3, and the deacetylation of H3K23 in gastric epithelial cells [88]. DNMT inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have been shown to be the most effective epigenetic drugs for treating GC in animal models. Nucleoside analogues of DNMTi (such as 5-azacitidine and 5-aza-dC or decitabine (DAC)) and non-nucleoside analogues of DNMTi (such as hydralazine) are separated according to their ability to integrate into freshly produced DNA [89]. A total of 485,512 methylation locations (482,421 at CpG sites and 3091 at non-CpG sites) from 55 cancer-related genes showed that epigenetic aberrations could alter various cancer-related pathways [87]. With the addition of the epigenetic drug to neoadjuvant epirubicin-oxaliplatin-capecitabine, a response rate of 67% was observed in patients with well-differentiated gastro-esophageal tumors, including 25% with a complete response. Hypomethylation of tumor-associated loci was observed at all 5-azacitidine doses, and the degrees of hypomethylation were correlated with a therapeutic response [90]. Gut bacteria can help fight cancer by producing bioactive metabolites that inhibit HDAC and HAT. These metabolites like SCFAs, propionate and butyrate can alter the epigenetic profile of cancer cells, making them more susceptible to treatment [91]. However, changing epigenetic profiles may represent new treatment approaches for GC. Cancer heterogeneity can be overcome and cancer homeostasis can be reprogrammed so that it is more likely to react to cytotoxic drugs or immune checkpoint inhibitors if epigenetic processes are targeted.
4.2 Epigenetic therapy in colon cancer
Colon cancer is one of the most fatal forms of the disease worldwide. Its genesis is linked to the collection of genetic and epigenetic modifications in the epithelial cells of the colon that cause them to morph into adenocarcinomas. In the last 10 years, there has been enormous progress in understanding cancer epigenetics, notably aberrant DNA methylation [92]. Microbial exposure was perceived to induce DNA hypomethylation, which increases the expression and activity of the DNA demethylase enzymes Tet3 and Dnmt1 [50, 93]. DNA methylation in colon biopsies is correlated with microbial composition, inflammation status, and disease classification in ulcerative colitis and Crohn’s disease patients [85]. Ulcerative colitis is associated with colorectal cancer, since Fusobacterium is associated with increased DNA methylation [94, 95, 96]. Yu et al. [71] demonstrated DNA methylation, particularly in the 3’CpG islands of glycosylation genes involved in cell maturation, which was substantially hampered in the absence of the intestinal microbiota. Changes in the fecal microbiota with decreased SCFA (acetate, propionate, and butyrate) have been attributed to the development and progression of colon cancer [97]. Studies have shown a low level of butyrate-producing bacteria in patients with colorectal cancer with a concurrent increase in mucin-degrading species such as Akkermansia muciniphila [98]. Probiotics can reduce the risk of colon cancer by improving intestinal microbiota balance. They can also reduce side effects of chemotherapy and radiation therapy by regulating neutrophil function and supporting anti-inflammatory activity by inducing TNF-α and miRNA-dependent expression of p21 gene [99, 100].
4.3 Epigenetic therapy in breast, ovarian, and endometrial cancer
Most ovarian cancers, 14–24%, are inherited diseases caused by gene mutations in BRCA1 and BRCA2 [101]. When BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, and FANCM are altered, genomic instability results in ovarian cancer with an early somatic mutation in TP53 [102]. The epigenetic environment of these tumors can contribute to increased immune activity. Although durable and long-lasting responses have been shown in solid tumors such as melanoma, lung cancer, and renal cell carcinoma [103], checkpoint blockade therapies have not been successful in ovarian cancer. Six genes that help control the cell cycle—BRCA1, CDKN2A, RASSF1A, LOTI, DAPK, and ICAM-l—are suppressed when hypermethylated gene promoters are detected in cancer. Studies have shown that extensive cessation of CpG hypermethylation in ovarian cancer leads to slower growth of cancer cells [104]. The research found that ITF2357 and 5-azacytidine (AZA) inhibited the DNMT1 enzyme and stimulated T cell participation by upregulating ERV expression in a mouse model of ovarian tumor. This activated a type I interferon response by increasing the expression of endogenous retroviruses (ERV), pieces of ancient viral DNA that make up 8% of our genome [105]. Moufarrij et al. [106] demonstrated that DNMTi decitabine successfully treats ovarian cancer that does not respond to chemotherapy. Furthermore, Cicek et al. [107] determined that the epigenetic drugs can enhance expression of tumor antigen NY-ESO-1 by changing its methylation status. It is important to study the combined pharmacodynamics and multifactorial mechanisms of epigenetic drugs when combined with targeted or immune therapies.
The gut microbiome has been observed to modulate estrogen metabolism [108]. Shimizu et al. [109] showed a significant increase in the reproductive capacity of germ-free mice with the introduction of microbials. Bacterial introduction normalized the estrous cycle and increased the copulation and implantation rates. An aggregate of enteric bacterial genes in the human gut microbiome can influence the estrabolome. Bacterial β-glucuronidases and β-glucuronides enhance estrogen deconjugation and conjugation [110]. Deconjugation results in the re-absorption of free estrogens, leading to the development of estrogen-driven cancers such as breast, ovarian, and endometrial cancers. Daidzein, a class of hydroxy isoflavones, is converted to dihydrodaidzein, S-(−)equol, and O-desmethyl angiotensin by the concentration of equol in the urine of intestinal bacteria has been correlated with a reduced risk of breast cancer. Therefore, epigenetic modifications can affect cancer progression [111].
4.4 Epigenetic therapy in liver and lung cancer
Tumor forms of cancer are thought to result from oncogene activation and TSG silencing due to mutations in epigenetic regulatory pathways. These epigenetic alterations can also be related to resistance to chemotherapy [112]. Studies show that methylation of certain genes (like CDK2A, p16, CDH13, RASSF1A, and APC) correlates with the recurrence of stage I non-small cell lung cancer (NSCLC) after surgical resection and epigenetic changes that affect p16, and p16 expression are associated with reduced survival after early-stage NSCLC resection [113]. In a phase I/II trial, patients with advanced untreated NSCLC received an 8-hour continuous infusion of high-dose decitabine (200 to 660 mg/m2). Only one patient completed more than one cycle, affecting the efficacy of treatment [114]. Pharmacodynamic studies have found that one-third of patients with lung cancer have higher levels of p16, MAGE-3, and NY-ESO-1 [115]. Histone modifications, HAT, and HDAC inhibitors are currently used in lung cancer treatment, but are still a few years away from being used as lung cancer biomarkers and guide therapy [116].
Dietary regulation, balanced gut microflora, and epigenetic modification can be useful in preventing liver and lung cancer. Studies have shown that chromatin modifications and other epigenetics (especially miRNA) are critical to the development of chronic obstructive lung disease (COPD) and lung cancer [117, 118]. SCFAs produced by the gut microbiota bind to the G protein-coupled receptor 43 (GPR43), affecting inflammatory responses [30]. GPR43 is important in reducing inflammation in models of colitis, arthritis, and asthma [68].
As scientists continue to explore the potential applications of epigenetic reprogramming, the possibilities are endless. This research could transform the way a disease is treated and prevent it from occurring in the first place. There is much to learn about this process, but the medical and scientific communities are excited to explore the potential of these organisms. Epigenetic detection has been an important advance in cancer research. By shedding light on how cancer develops and progresses, new treatments have been developed on the basis of these findings. In spite of many challenges like aberrant promoter methylation, inactivated mutations, tumor micro-environment, and external factors, these developments could have a significant impact on the fight against cancer. Epigenetic therapies are a promising new field of medicine that has the potential to revolutionize healthcare. Epigenetic drugs and other therapies are being studied for their potential to treat a wide range of diseases, including cancer. The gut microbiome can be used to manage and treat cancer and gut-related diseases. The bioactive metabolites produced by beneficial probiotic microbes affect the epigenome and the differentiation and functioning of various immune cells, enterocytes, and pancreatic cells. Modifying the intestinal microbiome by repairing dysbiosis through diet intervention or fecal transplants would be a promising approach to treating metabolic syndromes. Additionally, several clinical trials of epigenetic therapy are currently underway and could offer insight into the potential of epigenetic therapies. A new generation of epigenetic therapies could revolutionize healthcare care and change the way we live in the near future.
The authors are grateful to the editors for invitation of the book chapter. The authors SCR and SPR sincerely thank the founder of SVR BioScience Research Services, Dr. Sundru Manjulata Devi for giving an opportunity to contribute to the review.
Concept and design of the book chapter was conceived by SMD. The epigenetic changes and therapy was contributed by SMD. SCR contributed and formulated the for role of CRISR-Cas9 and SPR promoted the role of gut microbiota and probiotics in epigenetic changes. Editing, revision and final approval was made by SMD, SCR and SPR.
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