Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review)
- Authors:
- Published online on: December 19, 2023 https://doi.org/10.3892/ijo.2023.5605
- Article Number: 17
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Copyright : © Shao et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
Abstract
1. Introduction
Since 1960, when chemical modifications of RNA were first documented in detail as forms of epistatic modifications, >170 forms of RNA modifications, which have the role of maintaining mRNA stability and are involved in precursor shearing, transport and translation initiation of mRNA (1), have been identified (2). Of these modifications, the methylation modification of the nitrogen atom at position 6 of the RNA molecule adenine, i.e., N6-methyladenosine (m6A) modification, is the most widespread in eukaryotes (3). Although RNA methylation was discovered >60 years ago, owing to technical limitations, previous studies on epigenetic modifications in tumors have mostly focused on DNA methylation and histone modifications (4-7). It was not until 2012 when Meyer et al (8) first applied m6A-sequencing (seq) technology to determine the overall m6A levels of human and mouse genes at the transcriptional level on a large scale, and until 2015, when Linder et al (9) first used m6A individual-nucleotide-resolution cross-linking and immunoprecipitation-sequencing technology to achieve single-base m6A level detection that m6A research was gradually developed.
An increasing number of studies have found that abnormal m6A methylation is closely associated with the development, metastatic recurrence and treatment failure of various tumors (10,11).
Due to the relevance of epigenetic modifications in the extracellular environment, the complex heterogeneity of tumors and the potential of immunotherapy, research on m6A and tumors has predominantly focused on the immune microenvironment and immunotherapy (12,13). Indeed, only a few studies have really focused on the relationship between chemoresistance and m6A methylation, and even less on a specific single cancer entity.
Colorectal cancer (CRC) is the third most common cancer type worldwide (14), and significant amounts of research have been devoted to the development of novel antitumor agents in the form of immune agents, lysosomal viruses and vaccines; however, chemotherapy is still the dominant treatment strategy (15). By contrast, primary or secondary chemoresistance is the main cause of treatment failure in patients with advanced CRC, and another limitation of conventional chemotherapy is the lack of specific targets (16). Primary drug resistance refers to poor response of the tumor tissue to the conventional dose of drugs at the initial treatment, while secondary drug resistance refers to the expected state that the tumor tissue can shrink or necrosis under the action of the drug at the initial treatment, but the efficacy decreases or metastatic recurrence may even occur after long-term use of the drug. The difference lies in the response to the initial tumor treatment.
Epigenetic modifications of RNA are associated with sensitivity to multiple chemotherapeutic agents (17). Therefore, the present study focused on the relationship between aberrant m6A methylation modifications and chemotherapeutic response mechanisms in CRC (18-20) and various potential therapeutic measures targeting the m6A methylation process to seek novel strategies to improve the therapeutic effect pertaining to CRC.
Numerous scholars posit that the reversible and protein-regulatory properties of m6A methylation offer a promising approach to overcoming the current shortcomings in multiple cancer therapies (8). However, the real application of m6A methylation and clinical transformation must also solve a myriad of issues, including the following problems: i) M6A methylation as the most extensive RNA modification-how to focus and target the key molecules; ii) how to screen out the most accurately targeted drug candidates in each cancer species; and iii) how to specifically target the regulatory axis involved in m6A methylation to reverse drug resistance in tumors (21).
2. The m6A key enzyme in the development of CRC
Methyltransferases
The key m6A methylation enzymes can be classified into methyltransferases, methyl recognition enzymes and demethylases.
M6A methyltransferases mostly function as complexes [the m6A methyltransferase complex (MTC). The MTC mainly comprises methyltransferase-like 3 (METTL3), METTL14, vir like m6A methyltransferase associated (VIRMA), WT1 associated protein (WTAP), zinc finger CCCH-type containing 13 (ZC3H13), RNA binding motif protein 15 and Cbl proto-oncogene like 1 (HAKAI) (22,23). METTL3 was the first m6A methyltransferase identified and the only catalytic subunit of MTC, indicating that the presence and activation of METTL3 are the basis for m6A methylation. Although METTL3 can act independently of other m6A methyltransferases, its catalytic activity is much weaker than that of the MTC formed by wrapping it with other transferases (24). METTL14, as the primary RNA binding platform, forms a complex with METTL3 through 10 positively charged binding sites (Fig. 1), activating and enhancing METTL3 activity and promoting the recognition of RNA substrates, and thus enhancing MTC methylation efficiency (25,26). By contrast, WTAP is essential for promoting the enrichment of METTL3, METTL14 and other methyltransferases, transporting MTC into the nucleus and stabilizing MTC activity in the organism (27,28). VIRMA and ZC3H13 are relatively newly discovered m6A methyltransferases. VIRMA, also known as KIAA1429, which are the largest molecular weight proteins of MTC components known to date. VIRMA may be a scaffold for the MTC structure, connecting the immobilized WTAP, HAKAI and ZC3H13 to form an envelope structure capable of accommodating the METTL3-METTL14 complex (29). ZC3H13 is also a linking protein that bridges WTAP to the METTL3-METTL14 complex and facilitates the recognition of RNA substrates.
It was discovered that m6A methyltransferases are extensively involved in various stages of CRC, including tumor stemness, microenvironmental remodeling, drug resistance, metastasis and recurrence. Some of the roles and related pathway molecules are shown in Table I.
For a long time, the methyltransferase METTL3 has been regarded as a pro-oncogene (43,44). However, in recent years, a limited number of studies have found that under specific conditions, such as tumor starvation, METTL3 may also inhibit tumor development and development through the activation of the p38 signaling pathway and interference with the cell cycle to bring tumor cells into a dormant state (38,45). More interestingly, it has been suggested that METTL3 can function not only as a methyltransferase, but also as a methyl recognition enzyme independent of YTH N6-methyladenosine RNA binding protein F (YTHDF)1, capturing the recognition of mRNAs undergoing m6A methylation modification in the cytoplasm, promoting the recruitment of E74 like ETS transcription factor 3 (elF3) (46), drive β-linked protein trans-activation and upregulate c-Myc, VEGF, cyclin D7, MMP-3, c-Jun and other key genes of intestinal cancer malignant phenotypes (47).
Of note, m6A methylation is not only related to the modern medical concept, but also similar to certain Traditional Chinese Medicine (TCM) concepts (48,49).
In the concept of TCM, the function of various parts of the body is associated and influenced by the external environment. This is similar to epigenetics. If the external evil is more severe than the physical weakness, it is classified as excessive syndrome (ES) according to TCM concepts; if the two are of the same magnitude, it is classified as deficiency and excessive syndrome (DES); and if the physical weakness is more pronounced, it is defined as deficiency syndrome (DS). The early and early-middle stages of CRC often appear as ES or DES, while the late stages are DS (50,51). Under the guidance of these theories, TCM treatments need to be selected according to the different manifestations of different syndrome types in patients, so as to be used correctly (52).
It has been found that patients with CRC with different syndrome types have differences in gene expression, and elF3 and the downstream factors it regulates are typical representatives. High expression of the keratin 19, keratin 18, keratin 8, ELF3 and serpin family E member 1 genes is a potential marker to identify the TCM evidence type in CRC and, high expression of the ELF3 gene in CRC with DES or ES. High expression of mucin 2 and regenerating family member 4 in DES was mainly related to cell growth, as well as the MAPK and cyclic adenosine 3′,5′-monophosphate signaling pathways, while high expression of collagen type I alpha 2 chain and periostin genes in ES was mainly related to angiogenesis and the PI3K/AKT pathway and the caveolae-associated protein 2 and glutathione peroxidase 1 genes were highly expressed in DS and are mainly related to vomiting, platelet catabolism and endocytosis (50,53).
Whether m6A methyltransferases can function as methylation recognition enzymes or other epigenetic factors remains to be elucidated. The combination of classical medical theories, including TCM and epigenetic modifications, which are emerging molecular biology concepts, provides new perspectives for antitumor therapy and warrants further exploration (54,55).
Methyl recognition enzymes
The main function of methyl recognition enzymes is to recognize bases that undergo modification, thus activating downstream pathways and participating in biological processes, including mRNA translation, transcription, fission, and degradation. The core members include YTHDF1-3 and YTHDC1-3 (56-58). YTHDF2 and YTHDF3 accelerate the degradation and fission of modified mRNAs by recruiting the C-C chemokine receptor 4-negative regulator of transcription deadenosylation complex (59) and upregulating forkhead box O3 (FOXO3) expression (60), respectively.
Wang et al (61) found that YTHDF1 was significantly amplified and upregulated in CRC tissues, a phenomenon closely associated with the inflammatory cancer transformation of intestinal lesions and liver and lung metastases in patients with the aforementioned disease.
Although the exploration of RNA methylases is not widely performed in clinical practice, it is not only limited to discovery. There are also some small molecule drugs for methylation recognition enzymes such as YTHDF1, which is helpful for subsequent research.
The group of the above-mentioned study also developed a lipid nanoparticle-encapsulated Rho guanine nucleotide exchange factor 1 small interfering RNA drug for in vivo tumor therapy. YTHDF1 also up-regulates the transcription factor glucocorticoid modulatory element binding protein 2 of the adhesion-regulating molecule-1/nuclear factor kappa pathway, thereby activating the pathway to resist apoptosis and drive CRC progression (62). Ni et al (63) demonstrated that YTHDF3 is a novel target for the Yes-associated protein 1 (YAP) signaling pathway. A long noncoding RNA called growth arrest-specific transcript 5 (GAS5) binds directly to YAP, promoting YAP phosphorylation and attenuating YAP-mediated YTHDF3 transcription and allowing YTHDF3 to reversibly and selectively bind to GAS5, which undergoes m6A-methylation to trigger its decay and form a negative feedback loop. Although methylation recognition enzymes have been relatively poorly studied, they are indispensable for the proper binding of methyltransferases to the modified site.
Insulin-like growth factor 2 mRNA binding proteins (IGF2BPs) are also significant methyl recognition enzymes. They can specifically recognize and then bind directly to the m6A modification site, subsequently upregulating SOX2 to activate CRC stem cells (CSCs) (64). IGF2BP2 also can induce chemoresistance in CRC cells by activating the PI3K/AKT signaling pathway and enhancing aerobic glycolysis (65). However, these functions are still inseparable from the upstream regulation of METTL3.
Demethylases
Thus far, the knowledge of demethylases is limited and the only known demethylases are fat mass and obesity associated (FTO) and alkylation repair homolog 5 (ALKBH5). Demethylases are key to the reversibility of m6A methylation (66,67) and are able to complete the demethylation process by oxidizing m6A to N6-hydroxymethyladenosine and N6-formyladenosine (68-70). Conventionally, the reversibility of methylation modifications creates a window for reversing chemoresistance and increasing demethylase activity to tilt the reaction rate toward demethylation, thus facilitating the re-sensitization of drug-resistant cells to chemotherapy.
Relier et al (71) found that, although the overall FTO expression did not change significantly at different CRC stages, the subcellular localization of FTO shifted from strictly in the nucleus to the cytoplasm in the mucosa during metastatic CRC infiltration, which may be related to the tumor metastatic process. Meanwhile, FTO knockdown as performed in several different colon cancer cell lines, patient-derived cells and Patient-derived tumor xenograft animal models enhanced aldehyde dehydrogenase (ALDH) activity and promoted the CSC phenotype. Mice subjected to FTO silencing exhibited significant resistance to FOXFOL [50 μM 5-fluorouracil (5-FU) + 1 μM oxaliplatin (OXA)] as a first-line treatment, suggesting FTO is an important marker for predicting CRC metastasis and chemoresistance. Furthermore, Ruan et al (72) illustrated that, under hypoxic conditions in the tumor microenvironment, FTO leads to increased degradation of serine/threonine kinase receptor-associated protein as an E3 ligase-mediated ubiquitinated protein that promotes CRC metastasis. Further studies to elucidate the specific mechanisms of interaction between how FTO achieves metastasis from the nucleus to the cytoplasm according to the progression of CRC staging, how it identifies and specifically binds to its downstream targets and tumor microenvironment features, including those of hypoxia, FTO and CRC metastasis, and the response to therapeutic measures such as chemotherapy, are warranted. High expression and the methylation degeneration of ALKBH5 are strongly associated with Lynch syndrome (73) and silencing ALKBH5 facilitates an enhanced immune response, reduces lactate accumulation in the tumor microenvironment and increases infiltration of T-regulatory cells and myeloid-derived suppressor cell production (74). These findings are of great significance for slowing down the trend of CRC rejuvenation (75) and inducing the conversion of microsatellite stable-type CRC to 'hot tumors' to benefit from immunotherapy.
In brief, the m6A methylation key enzymes are widely involved in all aspects of CRC development and have considerable interventional value. Accordingly, it is reasonable to ask what the role of these enzymes is in the current mainstream chemotherapeutic benefits pertaining to CRC, and what the potential opportunities for intervention are.
3. Mechanisms of chemoresistance in CRC involving key m6A methylation enzymes
The mechanisms by which chemoresistance occurs in CRC are complex and there is no shortage of links involving m6A methylation enzymes. In particular, the mechanism of chemotherapy resistance due to an altered tumor microenvironment regulated by m6A methylation key enzymes has gained attention. The known molecular mechanisms underlying the m6A methylation of key enzymes that regulate common chemotherapeutic drug resistance in pan-cancer are presented in Fig. 2.
Li et al (64) found that METTL3 expression was elevated in both primary and metastatic CRC foci compared to normal tissue using a The Cancer Genome Atlas database analysis, and that patients with high METTL3 expression benefited less from chemotherapy when XELOX (OXA + capecitabine) and FOLFOX (5-FU + OXA) were used as first-line regimens. Chen et al (76) found that overexpression of IGF2BP1 promoted the colony-forming ability and resistance to 5-FU and etoposide in CRC cells.
As the study of m6A methyltransferase is the most extensive and because 5-FU and OXA are the most commonly used chemotherapeutic agents in the treatment of CRC, the resistance mechanisms associated with m6A methylation were found to be highly dependent on the regulation of METTL3 (54) (as shown in Fig. 2). Therefore, this study will further focus on the 5-FU and OXA resistance mechanisms of m6A methyltransferases, particularly METTL3, in CRC. Due to the high complexity of the many genes and proteins involved and the associated mechanisms, the present review categorizes these mechanistic processes into drug transporter protein-related, stem cell activity, EMT process and cellular autophagy, as illustrated in Fig. 3 and below.
Mechanisms associated with the microenvironment surrounding CRC cells
Tumor microenvironment refers to the special survival environment of tumor cells with their surrounding chemokines, apoptotic factors, immune cells, adhesion proteins, joint composition of metabolic disorders, defective apoptosis, lack of oxygen and acidification. Such a special environment is conducive to the evasion of tumor cells in response to therapy and epigenetic alterations such as m6A methylation induce the inevitable adaptation of tumor cells to this special environment.
Metabolic remodeling in CRC
Metabolic remodeling is one of the 14 features of the tumor environment (77) and CRC is characterized by abnormal active glycolipid metabolic rearrangement. Interference with metabolic pathways by inhibiting the activity of key enzymes of glycolysis and blocking oxidative phosphorylation pathways may improve the sensitivity of CRC-resistant cells to cisplatin and vincristine (78-80). Overexpression of METTL3 recruits YTHDF1 to trigger the translation of LDHA mRNA, catalyze glycolysis and increase the resistance of CRC cells to 5-FU (81). By contrast, knockdown of METTL3 reduces the protein translation efficiency of hypoxia-inducible factor-1α, inhibits the activity of lactate dehydrogenase A, hexokinase 2, GADPH and other key enzymes of glycolysis, and blocks the occurrence of the Warburg effect in intestinal cancer cells (82), thus re-sensitizing drug-resistant cells to chemotherapy. In addition, YTHDF1 and 2 are involved in the activation of transcription factor 4-mediated glutamine metabolism, and deletion of YTHDF1 and 2 enhances cisplatin tolerance in colorectal cancer (83,84).
Autophagy in CRC cells
Autophagy refers to the formation of autophagic lysosomes stimulated by various adhesion and apoptotic factors that transfer intracellular material into lysosomes for degradation. When the drug-tolerant persister (DTP) state is activated, key autophagy genes such as unc-51 like autophagy activating kinase 1 and autophagy related 2A are upregulated and when autophagy inhibitors are administered, cells exit the DTP state and cannot survive chemotherapy (85,86).
Hao et al (60) found that the m6A methylation recognition protein YTHDF3 is required for the maintenance of autophagy and that YTHDF3 depletion interrupts the formation of autophagosomes. Although YTHDF3 promotes and recognizes the translation of the autophagy gene FOXO3, it does not maintain its stability. Silencing METTL3 without interfering with YTHDF3 can still impair autophagy-lysosome synthesis and destabilize FOXO3 mRNA. Thus, the complete regulation of autophagy in CRC cells is influenced by METTL3 and the METTL3/YTHDF3 complex. Lin et al (87) demonstrated that the expression of light chain (LC)3B, a marker of autophagy activation, was positively correlated with the expression of FTO in normal and 5-FU-resistant CRC tissues and that FTO knockdown resulted in a significant increase in apoptosis, inhibition of autophagy in CRC cells and re-sensitization of drug-resistant cell lines to 5-FU.
Epithelial-mesenchymal transition (EMT)
A study from China published in 2020 found that METTL3 regulates the TGF-β and Snail pathways to affect EMT in intestinal cancer cells (88). EMT is also an important mechanism for the development of chemoresistance in CRC, indicating a decrease in adhesion factors such as epithelial surface calmodulin, detachment from basement membrane connections, and cytoskeletal and morphological convergence to mesenchymal features. Various molecules such as COP9 signalosome subunit 8, runt-related transcription factor 1, ubiquitin specific peptidase 43, histone deacetylase 2 and tumor microenvironment-associated fibroblasts can regulate EMT in CRC cells (89). When EMT occurs, the malignant phenotype of intestinal cancer becomes more prominent and resistant to OXA and 5-FU (90).
Mechanisms associated with the function of CRC cells themselves
Stem cell activity in CRC
CSCs are a special class of cells with self-healing and multi-differentiation potential. The most clinically relevant feature of CSCs is their ability to metastasize and evade standard chemotherapy (91). The differentiation homeostasis of this class of cells is usually regulated by the Wnt/β-catenin signaling pathway. Sec62 is a key protein in this pathway, and its increased expression enhances the sphere-forming ability of CSCs. Liu et al (92) found that Sec62 expression was positively correlated with METTL3 expression and that the METTL3-mediated accumulation of m6A methylation, which upregulates Sec62 levels, competitively disrupted the binding of β-linked protein and oncogene adenomatosis polyposis coli, leading to 5-FU resistance. METTL3-mediated m6A methylation accumulation also drives the methyltransferase recruitment of histone third subunit IV lysine (H4K3) to the promoter of leucine rich repeat containing G protein-coupled receptor 5 (LGR5), a colon cancer stem cell marker, leading to irinotecan and OXA resistance (93). Bai et al (94) found that silencing YTHDF1 downregulated CSC markers, including CD133, CD44, ALDH1, octamer-binding transcription factor 4 and LGR5, and inhibited Wnt/β-linked protein pathway activity in ex vivo experiments. Accordingly, it is proposed that YTHDF1 recognizes and promotes the translation of m6A-modified frizzled class receptor 9 and Wnt6 mRNAs, leading to aberrant activation of Wnt/β-linked protein signaling and ultimately affecting tumorigenicity, stem cell-like activity and response to chemical agents in CRC as a scientific hypothesis.
In other words, some researchers have found that m6A methylation key enzymes can regulate the expression of various CSC markers and, consequently, affect CSC activity and sensitivity to chemotherapeutic agents. However, the specific mechanisms involved remain to be further elucidated.
DNA damage repair (DDR)
Defects in the DDR pathway are a hallmark of genomically unstable tumors, and up to 15-20% of CRCs have DDR pathway defects (95,96). In the past, it was often thought that DDR pathway defects were mainly associated with peroxisome proliferators-activated receptors (PPAR) inhibitor efficacy. Furthermore, defects in the DDR pathway were primarily associated with the efficacy of PPAR inhibitors. Mechanism of action of common chemotherapeutic agents, including 5-FU and topoisomerase inhibitors, is related to the DDR pathway. METTL3 in the physiological state can promote cell repair after physical damage, including that caused by UV light. By contrast, METTL3 is pathologically upregulated in tumors, leading to an excessive rate of homologous recombination repair (HR), non-homologous end recombination and failure of chemotherapeutic drugs (97). Li et al (98) found that after METTL3 silencing treatment of HCT-8/5-FU resistant colon cancer cells, the resistant cells were able to be re-sensitized to 5-FU, while RAD51-associated protein 1, a key factor on the HR pathway, was downregulated. Zhang et al (99) discovered that METTL3 knockdown in OXA-resistant colon cancer cells also improved the chemosensitivity of resistant cells, while METTL3 overexpression restored the drug-resistant phenotype. Further sequencing suggested that the differentially expressed genes were mainly enriched in classical drug resistance pathways, including the Hippo and DDR pathways.
4. Therapeutic exploration of targeting key m6A methylation enzymes
Currently, the exploration of METTL3 inhibitors is being conducted mainly from the following three perspectives: Application of natural drug ingredients, small molecule drug synthesis development and clinical trials, and the combination of huge data with computer model predictions and screening of drug targets and pathways (as shown in Fig. 4).
Although m6A methylesterase inhibitors are currently less used in the treatment of CRC, the METTL3 inhibitor STM2457 has been reported to exhibit significant therapeutic effects in acute myeloid leukemia (100) and was able to reverse chemoresistance in small cell lung cancer (101) However, its derivative STC-15, the first clinical candidate for an oral agent targeting METTL3, is in phase I clinical trials for patients with advanced solid tumors (NCT05584111). Therefore, researchers have begun to explore the application of key m6A methylation enzyme modulators in solid tumors from multiple perspectives, including natural drug components, small molecule targeted drugs and programmed analysis of potential drug components using computerized big data. CRC has also received attention as a highly prevalent solid tumor, and an urgent clinical need to improve the efficacy of its treatments has emerged.
It has been suggested that most of the natural drug components that can regulate the action of m6A methylation key enzymes are polyphenols, alkaloids, flavonoids, anthraquinones and terpenoids (102). For instance, curcumin is a phenolic compound extracted from turmeric root that can reduce the expression of ALKBH5 and enhance the translation of tumor necrosis factor receptor associated factor 4 (TRAF4), prompting TRAF4 to bind to YTHDF6, a methyl recognition enzyme with m6A, and improve the efficiency of m6A methylation modification (103). Curcumin was also able to drive the conversion of microtubule-associated protein LC3-I to LC3-II or upregulate Beclin-1 to induce autophagy in CRC cells, reduce CSC generation and re-sensitize drug-resistant cells to 5-FU and OXA (104,105). The combination of curcumin with another polyphenol, resveratrol, could alter the distribution of key m6A methylation enzymes such as METTL3 and YTHDF2, reduce the overall m6A methylation level in the intestine and improve intestinal mucosal integrity (106).
An increasing number of studies support the anti-tumor effects of herbal medicines as epigenetic modification modulators, including turmeric, tannin, yam and Kalanchoe pinnata (107), which can target DNA (cytosine-5-)-methyltransferase 1 to inhibit P65 gene methylation and interfere with CRC cell infiltration and migration (108). Although the relationship between Chinese medicine and m6A methylation has not yet been fully elucidated, some studies have found that herbal extracts can regulate DNA methylation, including chaihu saponin (109), quercetin (110) and catechins (111). Flavonoid components such as chaihu saponin, quercetin and catechin can also increase the expression of METTL3 and METTL14 and decrease the methyl recognition proteins such as FTO and ALKBH5 (109,112).
As for small-molecule drug development, besides STM2457 and its derivative STC-15, modulators targeting methylation recognition enzymes are also under active development. An inhibitor of FTO called CS1 inhibited the proliferation of six CRC cell lines, including HT-29, COLO, HCT-116 and 5-FU-resistant cell lines (HCT-116/5FU). It also induced G25/M phase cell cycle arrest and promoted apoptosis of HCT-116 cells by downregulating doublecortin domain containing 2C (113).
Virtual screening and in vitro assays of 1,042 commercially available natural products by Du et al (114) identified quercetin as a natural inhibitor of METTL3, which binds to METTL3 to form stable protein-ligand complexes. Manna et al (115) identified hesperidin as a potent inhibitor of METTL3 by computer screening and molecular dynamics simulation. Deng et al (102) are also exploring the development of traditional drugs as novel and effective therapeutic agents to inhibit m6A modification-mediated tumor progression using the TCM Systematic Pharmacology Database and Analysis Platform, Indian Medicinal Plants Phytochemistry and Therapeutics database combined with artificial intelligence to build a framework for traditional or natural drug-based targeting of m6A drugs.
5. Discussion
M6A methylation modifications are a bridge between the tumor microenvironment and phenotypic alterations, including chemoresistance, the mechanisms of which are complex, and the knowledge of epigenetics is yet to be refined. Of note, it has been found that various epigenetic modifications are not completely isolated from each other and there is a strong correlation between m6A methylation and DNA methylation, which can specifically lead to increased DNA methylation at proximal sites when METTL3 is depleted, resulting in downregulated chromatin binding levels of fragile X mental retardation, autosomal homolog 1 and tet methylcytosine dioxygenase 1 (116). Although current studies on m6A methylation have started from a combination of various high-throughput screens, molecular deconstruction techniques and metabolic alteration assays, the specific mechanisms of the interactions between the various aspects of m6A methylation, how to accurately achieve a homeostatic balance between methylation and demethylation, and the specific mechanisms of migration, invasion resistance and other malignant phenotypes of tumors induced by key m6A methylation enzymes, as well as the regulation of the tumor microenvironment remain unresolved. More importantly, some of the currently developed m6A modification inhibitors and activators have poor target specificity, therapeutic efficacy, and safety and pharmacokinetic limitations. The large-scale development and application of artificial intelligence provide new opportunities to assist in the preclinical screening of more efficient drug components. More m6A methylation key enzyme modulators can enter clinical trials in the near future, providing an effective way to improve the treatment of CRC.
Of note, the present study had certain limitations. First, the specific expression of each key m6A methylase was not summarized and discussed. The expression of these methylation key enzymes in different cancer species and their close relation to clinical characteristics and prognosis was not focused on, and may be discussed in the future. The present review focused on summarizing some directions of the basic findings of each methylation key enzyme in CRC chemoresistance and the subsequent clinical transformation. Furthermore, the relationship between the complex immune microenvironment of CRC and key m6A methylases was not summarized and discussed. The present review focused on the relationship of the immune microenvironment with m6A modification, and indeed, considerable studies have focused on this aspect. This is another topic that is not very closely related to the focus of this paper, but the knowledge system is huge, so it was not discussed. In the future, a focus will be placed on the role of m6A in the immune microenvironment.
Availability of data and materials
Not applicable.
Authors' contributions
SCY and HYJ designed the study. SCY and TXK consulted the literature on the composition and role of key enzymes for m6A methylation. SCY, HYY and ZZ collected information on the relationship between key m6A enzymes and CRC and tracked the development of m6A-targeted drugs. ZYJ and FMZ categorized the retrieved materials according to year and differences in the types of key enzymes involved, and were responsible for the organization and design of the tables. SCY wrote this manuscript. HX, GT and LM critically reviewed the manuscript. HX directed and participated in information gathering, image conception and design, drawing figures and subsequent revision of the manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Abbreviations:
|
M6A |
N6-methyladenosine |
|
METTL3 |
methyltransferase-like 3 |
|
MTC |
m6A methyltransferase complex |
|
TCM |
Traditional Chinese Medicine |
|
CRC |
colorectal cancer |
|
DES |
deficiency and excessive syndrome |
|
YAP |
Yes-associated protein |
|
GAS5 |
growth arrest-specific transcript 5 |
|
FTO |
fat mass and obesity-associated protein |
|
PDX |
patient-derived tumor xenograft |
|
CSC |
colorectal cancer stem cell |
|
FOLFOX |
5-FU + oxaliplatin |
|
XELOX |
oxaliplatin + capecitabine |
|
DTP |
drug-tolerant persister |
|
EMT |
epithelial-mesenchymal transition |
|
H4K3 |
histone third subunit IV lysine |
|
DDR |
DNA damage repair |
|
HR |
homologous recombination repair |
Acknowledgments
Not applicable.
Funding
This study was supported by the National Natural Science Funds for Distinguished Young Scholar (grant no. 82204696), Grant of Nanjing University of Chinese Medicine (grant no. XPT82204696), the Nanjing Medical Science and Technology Development Project (grant nos. YKK21199 and YKK21201) and the Nanjing Health Young Talents Project of Jiangsu Province (grant no. QRX17187).
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