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Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

Abstract

RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N6-methyladenine (m6A) is the most abundant RNA modification. Methyltransferase-like 14 (METTL14) is the central component of the m6A methylated transferase complex, which is involved in the dynamic reversible process of m6A modification. METTL14 acts as both an oncogene and tumor suppressor gene to regulate the occurrence and development of various cancers. The abnormal m6A level induced by METTL14 is related to tumorigenesis, proliferation, metastasis, and invasion. To date, the molecular mechanism of METTL14 in various malignant tumors has not been fully studied. In this paper, we systematically summarize the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application. This study aims to provide new ideas for targeted therapy and improved prognoses in cancer.

Introduction

Among posttranscriptional modifications, more than 100 different types of RNA chemical modifications have been identified. N6-methyladenosine (m6A) modifications account for approximately 50% of all methylated RNA [1] and are one of the most common and abundant internal modifications [2, 3]. It is found in almost all eukaryotes and in some bacteria, viruses, yeasts, and plants [4, 5]. In 1974, the presence of a methyl substituent at N-6 of adenosine in nucleic acids was first identified in purified poly (A) RNA fragments [6, 7]. Subsequent studies confirmed that it is mainly present in the RRACH motif (where R = A/G, H = A/C/U) and is enriched in the 3' untranslated regions (UTRs), near the stop codon, and in the internal exon.

m6A methylation is widely present in mRNA, miRNAs, and long noncoding RNAs [8,9,10,11] and is involved in the basic pathophysiological metabolic processes of RNA, including splicing, nuclear output, translation, decay, folding, and RNA–protein interactions [12,13,14,15]. This newly identified type of modification plays an important role in regulating gene expression, which has become known as RNA epigenetics. In human physiology, m6A methylation plays a critical role in embryonic stem cell differentiation, meiosis, DNA repair, circadian rhythm, tissue development, and tumorigenesis [16,17,18,19]. Abnormalities in m6A methylation result in embryonic development disorders, failure of differentiation, neurological diseases, and tumorigenesis [20,21,22,23].

Functionally, m6A is divided into “writer” [24, 25], “eraser” [26], and “reader” [27] (Table 1, Fig. 1). m6A modification is a dynamically reversible pathway that mainly relies on erasers to encode m6A demethylase and remove m6A modifications in RNA molecules. At present, the known erasing genes include FTO and ALKBH5 [28]. FTO can affect the splicing and stability of mRNA by regulating m6A modification [29, 30], while ALKBH5-mediated demethylation affects the output and metabolism of mRNA and the assembly of mRNA processing factors in nuclear spots [31]. Both of these genes have dual regulatory effects on the occurrence and development of tumors. They catalyze the conversion of m6A to N6-hydroxymethyladenosine (hm6A) and hm6A to N6-formyladenosine (f6A) in two steps. Once formed, f6A spontaneously transforms into adenosine (A) [32]. In recent years, another demethylation transferase, AlkB homolog 3 (ALKBH3), has been identified, which may have a similar process [33, 34]. The m6A “reader” is responsible for identifying m6A methylated transcripts and generating functional signals, including the YTH domain family of proteins (YTHDC1/2, YTHDF1/2/3) [35,36,37,38,39], IGF2 mRNA binding protein (IGF2BP1/2/3) [40, 41], eukaryotic initiation factor 3 (eIF3) [42], and the heterokaryotic nuclear RNA protein family (HNRNPC, HNRNPG) [43,44,45]. These readers have been shown to mediate RNA splicing, nuclear export, translation efficiency, RNA stability, and RNA decay [37]. Different reading proteins recognize different m6A sites and perform different functions [46]. For example, YTHDF1/YTHDF3 identifies the m6A sequence in the ITGA6 3' UTR and promotes the translation of target genes that affect the malignant progression of bladder cancer [47]. YTHDF2 recognizes the methylation of SOCS2 and promotes its mRNA degradation to further regulate HCC cell proliferation and migration [48]. Methylation of RNA molecules is catalyzed by the methyltransferase complex (MTC), known as the "writer" protein, which consists of METTL3, METTL14, Wilms tumor 1 associated protein (WTAP), RNA-binding motif protein 15/15B (RBM15/15B), zinc finger CCCH-type containing 13 (ZC3H13) proteins, Vir-like m6A methyltransferase-associated (VIRMA/KIAA1429), and Cbl proto-oncogene like1 (CBLL1/Hakai) [49,50,51,52,53]. METTL3 is the only methyltransferase with catalytic activity, but it needs to bind to METTL14 to be effective [54]. The two combine to form a core complex (also known as the m6A-METTL complex, MAC) that catalyzes m6A methylation of most RNA. Other components of MTC form regulatory complexes (also known as m6A-METTL associated complexes, MACOM) that direct the core complex to specific site regions of RNA and provide binding sites, leading to increased catalytic activity [50, 55]. In addition, several studies have demonstrated the novel readers METTL16, METTL5, and ZCCHC4, which mediate m6A modifications of U6 snRNA, 18S rRNA, and 28S rRNA, respectively [56,57,58,59,60,61,62]. "Writers" and "erasers" can effectively install and remove mRNA methylation, and they work together to achieve a stable, dynamically balanced reversible process [63]. After the completion of the methylated splicing modification, the mature mRNA will undergo nuclear export and recognition by the reading protein, leading to further functional realization [64, 65].

Table 1 The functions of m6A enzymes in RNA metabolism
Fig. 1
figure 1

Molecular composition of the m6A RNA methylation. m6A is installed by “writers” (METTL3/14, WTAP, RBM15/15B, VIRMA, HAKAI, ZC3H13, METTL5/16, and ZCCHC4), removed by “erasers” (FTO, ALKBH5, and ALKBH3), and recognized by “readers” (YTHDC1/2, YTHDF1/2/3, IGF2BP1/2/3, HNRNPA2B1/C/G, and eIF3)

Although METTL14 does not have true catalytic activity, it serves as an important adapter for METTL3 activity to enhance methyltransferase activity by recognizing RNA substrates and methyl localization [66,67,68]. As an allosteric activator of METTL3 activity, METTL14, as an inactivated methyltransferase and allosteric activator of METTL3 activity, is involved in the development of various tumors. When METTL14 is mutated at cancer-associated sites, this reduces the catalytic activity and substrate specificity of the enzymes involved, leading to the reversal of methylation efficiency of consensus GGACU and non-consensus GGAUU sequences (decreased methylation at consensus sites and increased methylation at non-consensus sites), resulting in the occurrence of cancer [66, 69]. This paper reviews the research progress in understanding the role of METTL14 in the molecular mechanism of various malignant tumors and the biological processes involving METTL14. In addition, we discuss the structure and function of the METTL3-METTL14 heterodimer, the association of METTL14 with histone modification and potential therapeutic strategies for the dysregulation mechanisms of METTL14.

Structure and function of the METTL3-METTL14 heterodimer

METTL3 and METTL14 are essential components of the methyltransferases complex, which form a stable heterodimer in a 1:1 ratio [69]. Both of them contain the methyltransferase domain (MTD) [70]. MTD3 is comprised of 357–580 AA residues, which includes three loops (gate loop 1, gate loop 2, and interface loop), two CCCH motifs, catalytic sites (DPPW motif), and S-adenosylmethionine (SAM) binding sites [54, 70, 71]. Among these, SAM binding sites are mainly contained in loop 1 and loop 2, while the remaining rings, namely, the interface rings, have a large area and extensive contact with the METTL14 MTD [54]. METTL3 can transfer SAM methyl groups to the adenine base of RNA to produce homocysteine (SAH) to achieve methyl transfer [70]. In addition, its catalytic cavity has only the conservative motif EPPL [70]. Although MTD14 is structurally similar to MTD3, it lacks SAM binding sites, and thus it does not have catalytic activity [71]. However, METTL3 alone has weak catalytic activity, which is greatly increased only when combined with METTL14 [72]. Some studies have explained this phenomenon, suggesting that METTL14 provides an RNA-binding scaffold that plays an important role in maintaining the structural integrity of binary complexes and recognizing RNA substrates [73]. It is worth noting that some studies have reported that the C-terminal RGG domain of METTL14 contributes to its recognition function [74]. However, these studies are not sufficient. We still do not understand the mechanism by which this structure helps to identify targets, and whether there are other structures that help in this identification. If there are, it is of interest to know what are they and how they interact. In addition, it has been found in recent years that the METTL3-METTL14 complex has a certain repair effect on DNA damaged regions in vitro [75]. Under the same conditions, the METTL3-METTL14 heterodimer ssDNA methylation rate is much higher than that of ssRNA, and the single-stranded DNA has catalytic activity, while the double-stranded DNA does not [76]. This result provides new knowledge about the METTL3-METTL14 complex (Fig. 2).

Fig. 2
figure 2

The METTL3-MEETL14 methyltransferase complex. MTD3 of METTL3 is the real catalyst, while METTL14 stabilizes the structure and promotes RNA substrate recognition to improve methylation transferase activity. The catalytic cavity of METTL3 (DPPW motif) has an open conformation and binds to a cofactor (SAM), and METTL14 (EPPL motif) assumes a closed conformation. The two CCCH (ZnF) moieties of METTL3 are required for RNA substrate binding

METTL14 functions as an antioncogene

In most tumors, METTL14 acts as an antioncogene, downregulating the level of m6A in tumor cells by exerting its function as a m6A methyltransferase to suppress the occurrence and progression of tumors (Fig. 3).

Fig. 3
figure 3

The stimulatory role of METTL14 in human cancers, including AML, breast cancer, and pancreatic cancer

Colorectal cancer

Colorectal cancer (CRC) is a malignant disease with a high incidence worldwide. According to statistics, there are 945,000 new cases and nearly 700,000 deaths every year, making it one of the top four causes of cancer death [77,78,79]. Liu et al. confirmed that METTL14 expression was upregulated in CRC tissues, and survival analysis showed that the METTL14 expression level was significantly correlated with the prognosis of CRC [80]. Chen et al. further found that downregulation of METTL14 and m6A promoted the growth, invasion, and migration of cancer cells. The specific molecular mechanism is that overexpression of METTL14 affects the binding of DGCR8 and primiR-375 and regulates the level of miR-375. Furthermore, it further downregulates Yes-associated protein 1 (YAP1) to inhibit the growth of cancer cells and inhibit the invasion and migration of cancer cells by downregulating SP1 [81]. To better understand how METTL14 inhibits the malignant progression of cancer cells, some studies have also included reading proteins. For example, Wang et al. showed that methyl-CpG binding protein 2 (MeCP2) and METTL14 enhance the expression of Kruppel like factor 4 (KLF4) protein and mRNA in an IGF2BP2-dependent manner and inhibit the proliferation, metastasis, and invasion of CRC [82]. Chen et al. also confirmed that METTL14 mediates epithelial-mesenchymal transformation (EMT) and that PI3K/AKT signal transduction inhibition of CRC cell migration and invasion works partly through SRY-related high-mobility-group box 4 (SOX4). When METTL14 is knocked down, SOX4 mRNA is increased, and this process depends on YTHDF2 recognition [83]. Another study proved that lncRNA XIST was the downstream target gene of METTL14 through transcriptomic sequencing (RNA-seq) and methylated RNA immunoprecipitation (Me-RIP). When METTL14 was knocked down, the m6A level of XIST was downregulated and mRNA expression increased, thus promoting the malignant progression of CRC. In addition, METTL14 downregulates XIST-dependent m6A-YTHDF2 pathways [84]. Significant downregulation of METTL14 and YTHDC2 may be a potential prognostic biomarker for rectal cancer [85]. Moreover, Dong et al. revealed that in tumor-associated macrophages (TAMs) of CRC, knockout of METTL14 results in a decrease in m6A levels, an increase in EBI3, and dysfunction of antitumor T cells, which then promots the malignant progression of tumors [86]. In conclusion, studies have shown that the relationship between METTL14 and CRC is relatively extensive and involves the immune microenvironment. It is worth mentioning that studies that examine the METTL14 gene in the context of the immune system represent an interesting direction.

Liver cancer

Hepatocellular carcinoma (HCC) is a highly malignant tumor with high recurrence and metastasis rates and poor mortality. It is the most common fatal malignant tumor worldwide [87,88,89]. Although the risk indicators for HCC are well understood, the underlying molecular mechanisms remain unclear. Traditionally, it is believed that the occurrence of liver cancer is related to chromosome gain/loss and somatic mutation. In recent years, increasing evidence has shown that epigenetics plays a vital role in regulating the occurrence of liver cancer [90]. Shi et al. showed that METTL14 gene expression was significantly downregulated in HCC, which was associated with a poor prognosis in cancer patients. EGFR was identified as the downstream target gene of METTL14 by RNA sequencing and m6A sequencing, and METTL14 was shown to regulate the EGFR/PI3K/AKT signaling pathway in an m6A methylation-dependent manner, thereby inhibiting EMT and invasion of cancer cells [91]. However, in metastatic liver cancer, miR-126 is the target gene of METL14, and this pathway downregulates the expression of miR-126 to promote tumor metastasis by regulating the interaction between DGCR8 and primiR-126 [92]. Du et al. found that METTL14-mediated m6A modification maintained the stability of USP48 mRNA, thus participating in the regulation of HCC, and revealed that the METTL14-USP48-SIRT6 axis plays an inhibitory role by regulating glycolysis [93]. In addition, Li et al. proposed that METTL14 may inhibit the occurrence of HCC by upregulating the expression levels of cysteine sulfonate decarboxylase (CSAD), glutamic oxalacetic transaminase (GOT2), and cytokine signaling inhibitor 2 (SOCS2) [94]. These studies show that METTL14 has a significant impact on liver cancer.

Breast cancer

Breast cancer remains a serious challenge for women around the world, with a five-year survival rate of less than 30% for patients with advanced cancer [95]. Further research on the molecular mechanism of breast cancer is becoming increasingly important to improve the survival rate and clinical prognosis. Several studies have demonstrated reduced METTL14 expression in breast cancer tissues [96, 97]. Its expression level was shown to be negatively correlated with tumor grade [98]. The lower the expression level was, the worse the prognosis [97]. Overexpression of METTL14 can lead to a decrease in m6A levels and inhibit the migration and proliferation of cancer cells [96].

Endometrial carcinoma

Endometrial cancer (EC) is a common malignant gynecological tumor worldwide. Even in early-stage cancer, routine surgery has a great impact on the fertility of patients, and the development of effective interventions is of great importance [99, 100]. Ma et al. reported that m6A RNA methylation was closely associated with the clinicopathological stage and prognosis of endometrial cancer and that METTL14 was used as a potential marker for the diagnosis and prognosis of endometrial cancer [101]. Liu et al. found that the R298P mutation in the key component of METTL14 leads to a reduction in m6A methylation and activation of the AKT pathway, thereby promoting the proliferation and migration of endometrial cancer cells. The increase in AKT activity depended on the decrease in PHLPP2 expression and the increase in mTORC2 expression [102].

Bladder cancer

Bladder cancer (BC) is the most universal tumor of the urinary system and has become the fifth most common cancer in the United States, producing an estimated 81,400 cases in 2019 [22, 103]. Gu et al. found that low expression of METT14 in BC and bladder tumor-initiating cells (TICs), decreased m6A levels, and m6A levels were associated with clinical severity and prognosis. Knockout of METTL14 enhances Notch1 expression and stability, promoting the development of BC and bladder TIC self-renewal [104]. The METTL14-m6A-Notch1 pathway plays a critical role in bladder tumorigenesis and bladder TICs. Zhang et al. revealed that isorhapontigenin (ISO) inhibited the migration, invasion, and EMT of BC cells by upregulating METTL14 mRNA expression and decreasing vimentin protein levels by activating the transcription factor FOXO3a [105].

Neuroblastoma

Neuroblastoma (NB) is the most common tumor in infants and young children. It originates from the sympathetic ganglion and bilateral adrenal glands and has the highest morbidity and mortality in infancy [106, 107]. Wang et al. proposed that METTL14 combined with WTAP, HNRNPC, YTHDF1, and IGF2BP2 contributed to the prognosis of NB and could be used as new targets for clinical treatment [107]. Our group first found that some SNPs in the METTL14 gene were closely associated with the risk of neuroblastoma. METTL14 gene rs298982 G > A and rs62328061 A > G were significantly associated with reduced susceptibility to neuroblastoma, while rs9884978 G > A and rs4834698 T > C were associated with increased susceptibility to neuroblastoma [108].

Glioblastoma

Glioblastoma, which is the most common primary brain tumor, involves self-renewing glioblastoma stem cells (GSCs). The high mortality rate of glioblastoma is largely due to the tumor heterogeneity and therapeutic resistance of GSCs [109, 110]. Studies have shown that METTL14 gene knockout significantly promotes the generation and development of GSCs, possibly by affecting the enrichment of ADAM19 m6A to promote the expression of ADAM19, resulting in the self-renewal and tumorigenesis of GSCs [111].

Kidney cancer

Kidney cancer, also known as renal cell carcinoma (RCC), is a malignant tumor with the highest mortality rate in the genitourinary system, among which the most common pathological type is clear cell carcinoma of the kidney (ccRCC) [112]. According to statistics, the United States reports 73,820 cases a year and an estimated 14,770 deaths [113]. Compared with normal kidney tissue, the METTL14 mRNA level was significantly reduced in ccRCC [114]. Gong et al. confirmed that knockdown of METTL14 reduced m6A levels and increased mRNA and protein levels of P2RX6, which then promoted the migration and invasion of RCC through the ATP-P2RX6-Ca2+-P-ERK1/2-MMP9 signaling pathway [115]. Liu et al. found that METTL14 inhibited the proliferation and migration of renal carcinoma by inhibiting the expression of long noncoding RNA nuclear enriched abundant transcript 1_1 (NEAT1_1) by YTHDF2 [116]. METTL14 may be an independent prognostic indicator of RCC and ccRCC in univariate and multivariate Cox regression analyses [117,118,119,120]. The reduced METTL14 expression predicts a poor prognosis of the tumor. Studies have suggested that in RCC, the miRNA/mRNA-hsa-miR-1307- 3p/METTL14 pathway may regulate the occurrence and development of tumors and play an important role in clinical applications [121]. In addition, some studies have found that METTL14 is positively correlated with PTEN [114], which indicates that METTL14 plays an inhibitory role in RCC by regulating PTEN. Notably, Zhang et al. revealed that knockdown down of METTL14 enhances the stability of bromodomain PHD finger transcription factor (BPTF) mRNA and activates downstream targets such as enolase 2 and SRC proto-oncogene nonreceptor tyrosine kinases, leading to glycolytic reprogramming that drives RCC metastasis [122]. This provides a mechanism for the synergistic effect of m6A modification and glycolysis.

Papillary thyroid carcinoma

The most common type of thyroid cancer is papillary thyroid carcinoma (PTC), with an incidence of more than 80% and a 5-year survival rate of more than 97% with a good prognosis [123]. Zhang et al. demonstrated through RIP and RNA pull-down analysis that lncRNA OIP5-AS1 is a gene downstream of METTL14, and that the overexpression of METTL14 regulates MEK/ERK and EGFR pathways through OIP5-AS1/miR-98/ADAMTS8, thus promoting the malignant behavior of PTC cells [124].

Leukemia

Acute myeloid leukemia (AML) is a common and deadly tumor of the blood system [125]. Alterations in m6A levels can affect cell fate and differentiation status [126]. Sun et al. found that METTL14 levels were decreased in E/R positive patients compared with the control group, and it was speculated that the downregulation affected m6A modification in related cancer cells, thereby promoting the occurrence of AML [127]. A five-center case–control study found that METTL14 gene rs298982 G/A and rs1064034 T/A were significantly associated with a reduced risk of ALL in children [128]. METTL14 may be a potential biomarker for the prognosis of ALL.

Other cancers

In addition to the abovementioned tumors, METTL14 also acts as a tumor suppressor in other tumors. In lung adenocarcinoma (LUAD), Wang et al. found that METTL14 enhanced the stability of human leukocyte antigen complex group11 (HCG11) mRNA and inhibited the growth of lung adenocarcinoma via IGF2BP2/LATS1 [129]. The characteristic expression of the m6A regulatory factor in castration-resistant prostate cancer (CRPC) and prostate cancer (PCa) was analyzed. METTL14 was downregulated and correlated with lymph node metastasis of CRPC and was negatively correlated with the Gleason grade in PCa [130]. METTL14 was downregulated in triple-negative breast cancer (TNBC) [118], esophageal cancer (EC) [131], gastric cancer [132], osteosarcoma (OS) [133],Wilms tumor, [134] and oral squamous cell carcinoma (OSCC) [135], and low METTL14 expression was related to poor prognosis. Notably, it has been confirmed that METTL14 knockout can activate Wnt and PI3K-Akt signals to promote the growth and invasion of gastric cancer cells [132]. Of course, these findings of MTTL14 need to be confirmed by subsequent studies.

METTL14 acts as an oncogene

Although many studies have shown an inhibitory effect on cancer, METTL14 has also been shown to stimulate the development and progression of tumors in some cases (Table 2). Wang et al. reported that m6A levels were elevated in most pancreatic cancer samples and that METTL14 expression was significantly associated with survival. METTL14 overexpression reduces PERP mRNA and protein levels and promotes tumor cell migration and colony formation [136]. The CLK1-SRSF5 axis promotes the proliferation, migration, invasion, and colony formation of pancreatic cancer cells by inhibiting METTL14Exon10+ exon skipping and increasing the m6A level [137]. METTL14 overexpression regulates the expression of hsa-miR-146a-5p through m6A modification, thereby promoting breast cancer invasion and migration [138]. Sun et al. found that LINC00942, as an oncogene in the occurrence and development of BRCA tumors, promotes METTL14-mediated m6A modification and regulates the mRNA stability and protein expression of the downstream genes CXCR4 and CYP1B1, thus promoting tumor growth and development. A new LINC00942-METTL14-CXCR4/CYP1B1 pathway was verified, providing a new approach for the diagnosis and treatment of BRCA [139]. Subsequently, Peng et al. found that the oncogene AURKA enhances the stability of DROSHA mRNA and promotes the oncogenic properties of the DROSHA-STC1 axis by inhibiting the ubiquitination-mediated degradation of the METTL14 protein and improving the recognition ability of IGF2BP2, leading to the malignant progression of breast cancer [140]. Therefore, it is reasonable to speculate that the upregulation of m6A in peripheral blood may be a new biomarker for breast cancer and that the upregulation of METTL14 has a better diagnostic role in peripheral blood BC screening [141]. Similarly, Zhao et al. investigated whether m6A RNA methylation-related proteins can effectively predict the prognosis of head and neck squamous cell carcinoma (HNSCC). The results showed that the upregulation of METTL14 and WTAP may have a certain guiding significance for prognosis prediction [142]. In addition, Weng et al. reported that METTL14 blocked bone marrow differentiation and promoted cell proliferation in normal hematopoietic stem/progenitor cells (HSPCs) and AML. This occurred because METTL14-mediated m6A modification improves the mRNA stability and translation of the downstream target gene MYC/MYB, whereas METTL14 is negatively regulated by SP1. In other words, when SPI1 expression is inhibited, METTL14 upregulates MYC/MYB expression, leading to blocked bone marrow differentiation and cancer [18]. In addition, Martin et al. demonstrated that lowering METTL14 and METTL3 levels promoted bone marrow differentiation [143]. The carcinogenic role of METTL14 in leukemia was emphasized (Fig. 4).

Table 2 The function of METTL14 as an m6A methyltransferase in human cancer
Fig. 4
figure 4

The suppressive role of METTL14 in human cancers, including colorectal cancer, liver cancer, endometrial cancer, bladder cancer, glioblastoma, renal carcinoma, PTC, gastric cancer, breast cancer, skin tumor, and lung adenocarcinoma

Interaction of METTL14 with histone modifications

In a study of embryonic neural stem cells (NSCs), Wang et al. found that knockdown of METTL14 significantly increased the level of acetylation of histone H3 at lysine 27 (H3K27ac), trimethylation of histone H3 at lysine 4 (H3K4me3), and trimethylation of histone H3 at lysine 27 (H3K27me3) and reduced the proliferation ability of neural stem cells. It was further verified that METTL14 regulates histone modification by enhancing the stability of H3K27ac CBP/p300 mRNA [144]. The interaction between m6A and histone modification was revealed for the first time. Chen et al. reported that lysine-specific histone demethylation 5C (KDM5C) mediates the demethylation of H3K4me3 in the METTL14 promoter in colorectal cancer and inhibits the transcription of METTL14 [82]. On this basis, Wang et al. found that arginine methylation in the C-terminal region of METTL14 promoted the binding of METTL14 to RNA substrates, METTL3-14 methyltransferase activity and METTL14 interaction with RNA polymerase II [145]. Huang et al. demonstrated that H3K36me3 can directly bind to MTC, and that METTL14 recognizes the core region of H3K36me3 and collaborates with RNA polymerase II to induce methylation of new RNA [146, 147]. In conclusion, the above findings reveal the cross-talk between histone modification and m6A modification at the level of epigenetic modification, revealing a new gene regulation mechanism and a further understanding of the recognition mechanism of METTL14.

Potential clinical treatments

By exploring the relationship between the immune system and tumorigenesis, immunotherapy has become an unprecedented treatment for many cancers [148]. Increased RNA methylation in anticancer immunotherapy affects immune responses [149]. Wang et al. found that inhibition of m6A mRNA modification by deletion of METTL14 and METTL3 enhanced the response to programmed cell death-1 (PD-1) therapy in colorectal cancer. The proliferation of CD8+T cells and the production of interferon (IFN)-C, CXCL9, and CXCL10 were also induced. It also promotes the accumulation of CD8+ and CD4+ effector T cells, which inhibit tumor growth, and enhance the efficacy of immunotherapy [150, 151]. In the treatment of AML, all-trans retinoic acid/arsenic trioxide (ATO) [152], differentiation inducers (OP9 medium) [153], PMA [154], and all-trans retinoic acid (ATRA) [155] have been reported to significantly reduce m6A levels and the expression of METTL14, thereby promoting myeloid differentiation and inhibiting leukemia growth [156]. In pancreatic cancer, knockout of METTL14 enhances the sensitivity of cancer cells to cisplatin by inducing apoptosis and autophagy through the mTOR signaling pathway [157] and inhibits the expression of cytidine deaminase (CDA), improving the sensitivity of drug-resistant cells to gemcitabine [158]. These studies demonstrate the importance of METTL14 inhibitors in the treatment of tumors. In addition, a recent study found that METTL14 regulates DDB2 translation to promote global genomic repair (GGR) and inhibits ultraviolet B (UVB) radiation to reduce the incidence of skin tumors [159]. Therefore, screening for and designing more effective METTL14 protein inhibitors and activators are expected to provide new anticancer drugs, and targeted therapies in combination with other drugs may become a panacea for controlling many diseases and other forms of cancer (Fig. 5).

Fig. 5
figure 5

The potential clinical role of METTL14 and METTL3 in certain cancers, including pancreatic cancer, skin tumor, colorectal cancer, and AML

Conclusions and prospects

The occurrence and development of cancer are mainly caused by abnormal genetic changes and epigenetic abnormalities. Abnormal inheritance includes gene mutation, deletion, amplification, and chromosomal translocation [40]. Epigenetics includes DNA, RNA, and histone modifications [160,161,162,163]. m6A methylation is the most common internal modification of RNA and is of great significance for gene expression regulation [164, 165]. Changes in m6A-related genes or proteins affect a variety of biological processes that involve m6A methylation, including viral infection [166], stress [167], heat shock [15], DNA damage [168], and the occurrence and development of cancer. It is worth noting that METTL14 can function independently of m6A. For example, Liu et al. found that the METTL3-METTL14 complex promotes transcription of the SASP gene and enhances immune surveillance, independent of changes in m6A levels [169]. This article reminds us that hotspot proteins should be studied from multiple perspectives with innovative perspectives.

In recent years, with an increasing number of studies on METTL14, some breakthroughs have been made in some aspects, such as mechanisms and pathways of cancer and related metabolic processes, but at the same time, many problems have been exposed. First, METTL14 can recognize the structural support and recognition function of METTL3, but the specific structural basis and molecular mechanism of this recognition and support remain unclear. It is also unclear how METTL14 interacts with other MTC components during tumor development. Second, the METTL3-14 complex has been thought to play a synergistic role. However, studies have shown that METTL3 and METTL14 have opposite regulatory effects on HCC [170]. We hypothesized that METTL3 and METTL14 may have different target preferences and thus trigger different pathway effects. Of course, this requires further experimental verification. In addition, the m6A locus of the METTL14 target gene has not been mapped in detail in specific studies of the METTL14 pathway. Finally, it is particularly emphasized that METTL14 has a dual regulatory effect on tumors, and attention should be paid to the use of METTL14 activators or inhibitors to avoid the occurrence of other tumors.

In summary, METTL14 plays an important role in a variety of tumors, regardless of whether they are dependent on m6A modification. We look forward to further studies to optimize a targeted METTL14 treatment and enable its use widely in clinical practice.

Availability of data and materials

Not applicable.

Abbreviations

METTL14:

Methyltransferase-like14

UTR:

Untranslated region

MTC:

Methyltransferase complex

hm6A:

N6-hydroxymethyladenosine

f6A:

N6-formyladenosine

ALKBH3:

AlkB Homolog 3

IGF2BP:

IGF2 mRNA binding protein

eIF3:

Eukaryotic initiation factor 3

WTAP:

Wilms tumor 1 associated protein

RBM:

RNA-binding motif protein

ZC3H13:

Zinc finger CCCH-type containing 13

VIRMA:

Vir-like m6A methyltransferase-associated

CBLL1:

Cbl proto-oncogene like1

MAC:

M6A-METTL Complex

MACOM:

M6A-METTL associated complexes

MTD:

Methylation transferase domain

SAM:

S-adenosylmethionine

CRC:

Colorectal cancer

YAP:

Yes-associated protein1

SOX4:

SRY-related high-mobility-group box 4

EMT:

Epithelial-mesenchymal transformation

KLF4:

Kruppel like factor 4

TAM:

Tumor-associated macrophage

HCC:

Hepatocellular carcinoma

CSAD:

Cysteine sulfonate decarboxylase

GOT2:

Glutamic oxalacetic transaminase 2

SOCS2:

Cytokine signaling inhibitor 2

AML:

Acute myeloid leukemia

EC:

Endometrial cancer

BC:

Bladder cancer

TICs:

Tumor-initiating cells

ISO:

Isorhapontigenin

GSCs:

Glioblastoma stem cells

RCC:

Renal cell carcinoma

PTC:

Papillary thyroid carcinoma

PCa:

Prostate cancer

NEAT:

Nuclear enriched abundant transcript

BPTF:

Bromodomain PHD finger transcription factor

LUAD:

Lung adenocarcinoma

HCG11:

Human leukocyte antigen complex group11

OSCC:

Oral squamous cell carcinoma

CRPC:

Castration-resistant prostate cancer

TNBC:

Triple-negative breast cancer

EC:

Esophageal cancer

OS:

Osteosarcoma

MeCP2:

Methyl CpG-binding protein 2

HNSCC:

Head and neck squamous cell carcinoma

KDM5C:

Lysine-specific histone demethylation 5C

H3K4me3:

H3 lysine 4 trimethylation

PD-1:

Programmed cell death-1

ATRA:

All-trans retinoic acid

CDA:

Cytidine deaminase

UVB:

Ultraviolet B

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Acknowledgements

We apologize to the colleagues whose work could not be cited due to space constraints.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82173593, 82002636, 82002635), China Postdoctoral Science Foundation (2020T130132, 2020M682668), and Guangzhou Science and Technology Project (202102020421).

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QG, HRL and LM collected the related literature. QG, HRL, LM, HQG and YPC wrote the manuscript. ZJZ and JH participated in the design of the review and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Zhenjian Zhuo or Jing He.

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Guan, Q., Lin, H., Miao, L. et al. Functions, mechanisms, and therapeutic implications of METTL14 in human cancer. J Hematol Oncol 15, 13 (2022). https://doi.org/10.1186/s13045-022-01231-5

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Keywords

  • RNA modification
  • m6A
  • METTL14
  • Cancer
  • Drug discovery