RNA N6-methyladenosine (m6A) plays diverse roles in RNA metabolism and its deregulation contributes to tumor initiation and progression. Clear cell renal cell carcinoma (ccRCC) is characterized by near ubiquitous loss of VHL followed by mutations in epigenetic regulators PBRM1, SETD2, and BAP1. Mutations in SETD2, a histone H3 lysine 36 trimethylase (H3K36me3), are associated with reduced survival, greater metastatic propensity, and metabolic reprogramming. While m6A and H3K36me3 deregulation are separately implicated in renal tumorigenesis, H3K36me3 may participate directly in m6A targeting, but the m6A-H3K36me3 interplay has not been investigated in the context of ccRCC. Using RCC-relevant SETD2 isogenic knockout and rescue cell line models, we demonstrate a dynamic redistribution of m6A in the SETD2 depleted transcriptome, with a subset of transcripts involved in metabolic reprogramming demonstrating SETD2 dependent m6A and expression level changes. Using a panel of six histone modifications we show that m6A redistributes to regions enriched in gained active enhancers upon SETD2 inactivation. Finally, we demonstrate a reversal of transcriptomic programs involved in SETD2 loss mediated metabolic reprogramming, and reduced cell viability through pharmacologic inhibition or genetic ablation of m6A writer METTL3 specific to SETD2 deficient cells. Thus, targeting m6A may represent a novel therapeutic vulnerability in SETD2 mutant ccRCC.

The gut microbiota undergoes continuous variations among individuals and across their lifespan, shaped by diverse factors encompassing diet, age, lifestyle choices, medication intake, and disease states. These microbial inhabitants play a pivotal role in orchestrating physiological metabolic pathways through the production of metabolites like bile acids, choline, short-chain fatty acids, and neurotransmitters, thereby establishing a dynamic "gut-organ axis" with the host. The intricate interplay between the gut microbiota and the host is indispensable for gut health, and RNA N6-methyladenosine modification, a pivotal epigenetic mark on RNA, emerges as a key player in this process. M6A modification, the most prevalent internal modification of eukaryotic RNA, has garnered significant attention in the realm of RNA epigenetics. Recent findings underscore its potential to influence gut microbiota diversity and intestinal barrier function by modulating host gene expression patterns. Conversely, the gut microbiota, through its impact on the epigenetic landscape of host cells, may indirectly regulate the recruitment and activity of RNA m6A-modifying enzymes. This review endeavors to delve into the biological functions of m6A modification and its consequences on intestinal injury and disease pathogenesis, elucidating the partial possible mechanisms by which the gut microbiota and its metabolites maintain host intestinal health and homeostasis. Furthermore, it also explores the intricate crosstalk between them in intestinal injury, offering a novel perspective that deepens our understanding of the mechanisms underlying intestinal diseases.

RNA methylation is a vital epigenetic modification that regulates gene expression by influencing RNA processes such as transcription, degradation, translation, and transport. Aberrant methylation, including modifications like m6A, m5C, m1A, m7G, and m3C, is closely linked to tumorigenesis and progression. Liquid biopsy, a non-invasive technique analyzing tumor markers in body fluids, offers significant potential for early diagnosis and dynamic monitoring. In this context, RNA methylation, due to its tumor-specific properties, is emerging as a valuable marker. However, significant challenges remain in its clinical application. This review explores the roles of RNA methylation in cancer, recent advances in detection technologies, and its potential as a liquid biopsy marker in tumor management. It highlights its promising applications in cancer diagnosis, prognosis, and personalized treatment in the era of precision oncology.

Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, with metabolic reprogramming recognized as a central driver of tumor progression and therapeutic resistance. Among the key regulatory layers, N6-methyladenosine (m6A) RNA modification-mediated by methyltransferases (writers such as METTL3/14), RNA-binding proteins (readers like YTHDFs and IGF2BPs), and demethylases (erasers including FTO and ALKBH5), plays a pivotal role in controlling gene expression and metabolic flux in the tumor context. Concurrently, the gut microbiota profoundly influences GI tumorigenesis and immune evasion by modulating metabolite availability and remodeling the tumor microenvironment. Recent evidence has uncovered a bidirectional crosstalk between microbial metabolites and m6A methylation: microbiota-derived signals dynamically regulate m6A deposition on metabolic and immune transcripts, while m6A modifications, in turn, regulate the stability and translation of key mRNAs such as PD-L1 and FOXP3. This reciprocal interaction forms self-reinforcing epigenetic circuits that drive tumor plasticity, immune escape, and metabolic adaptation. In this review, we dissect the molecular underpinnings of the microbiota-m6A-metabolism axis in GI cancers and explore its potential to inform novel strategies in immunotherapy, metabolic intervention, and microbiome-guided precision oncology.

N6-methyladenosine (m6A) methylation is the most prevalent and abundant internal modification of mRNAs and is catalyzed by the methyltransferase complex. Methyltransferase-like 3 (METTL3), the best-known m6A methyltransferase, has been confirmed to function as a multifunctional regulator in the reversible epitranscriptome modulation of m6A modification according to follow-up studies. Accumulating evidence in recent years has shown that METTL3 can regulate a variety of functional genes, that aberrant expression of METTL3 is usually associated with many pathological conditions, and that its expression regulatory mechanism is related mainly to its methyltransferase activity or mRNA posttranslational modification. In this review, we discuss the regulatory functions of METTL3 in various diseases, including metabolic diseases, cardiovascular diseases, and cancer. We focus mainly on recent progress in identifying the downstream target genes of METTL3 and its underlying molecular mechanisms and regulators in the above systems. Studies have revealed that the use of METTL3 as a therapeutic target and a new diagnostic biomarker has broad prospects. We hope that this review can serve as a reference for further studies.

Ribosomal protein S6 kinase B1 (S6K1) is frequently amplified and correlates with drug resistance and poor prognosis in patients with breast cancer. Although S6K1 functions primarily in the process of translation, the genome-wide translational profiles regulated by S6K1 remain unclear. This study sought to clarify the pivotal role of S6K1 in translational regulation and investigate its novel targets in breast cancer.

Ribosome profiling sequencing (Ribo-seq) was performed to explore genome-wide translational profiles regulated by S6K1 in breast cancer cells. Integrated multiomics analyses, including Ribo-seq, RNA sequencing, and mass spectrometry, were employed to identify a new target of S6K1 translational regulation, the autophagy-related gene clusterin (CLU). Western blotting and immunofluorescence were utilized to confirm that S6K1 regulated CLU translation, thus influencing autophagy in breast cancer cells. Bafilomycin A1 (a late-stage autophagy inhibitor) was used to demonstrate that S6K1 regulated autophagosome formation in breast cancer cells through affecting the translation of CLU.

S6K1 depletion resulted in the downregulation of global messenger RNA (mRNA) translation and affected translation in multiple pathways that play crucial roles in carcinogenesis, with autophagy-related pathways being the most prominently affected. The role of S6K1 in autophagy was further confirmed in breast cancer cells, and CLU was identified as a novel target regulated by S6K1 at the translational level. Additionally, the overexpression of S6K1 promoted the translation of CLU, thus facilitating the formation of autophagosomes.

This study demonstrated that the overexpression of S6K1 promoted autophagy in breast cancer cells by facilitating the translation of the autophagy-related gene CLU.

RNA epigenetics is gaining increased attention for its role in the initiation, metastasis, and drug resistance of tumors. These studies have primarily focused on m6A modification. However, despite being the second most abundant modification found in RNA, the role of m5C modification in prostate cancer remains largely unexplored. Here, we predict an RNA m5C methyltransferase, NSUN2, as a potential therapeutic target for prostate cancer using various bioinformatics approaches, and verify the potential of NSUN2 as a target through multiple preclinical models. Mechanistically, NSUN2 enhances the stability of TRIM28 mRNA by adding m5C modification, promoting the expression of TRIM28. Concurrently, FOXA1, a prostate cancer lineage-specific transcription factor, transcriptionally activates the expression of NSUN2. Our study confirms the clinical potential of targeting RNA epigenetics for the treatment of prostate cancer and elucidates, mechanistically, how RNA epigenetics participates in the complex biological activities within tumors via the FOXA1-NSUN2-TRIM28 axis.

Hepatocellular carcinoma (HCC) is a highly heterogeneous, proliferative, and aggressive malignancy of the digestive system. MicroRNAs (miRNAs) are expected to be a new target for the treatment of HCC. Crosstalk between N6-methyladenine (m6A) modification and miRNAs are involved in HCC progression. This study aimed to explore the role of miR-1293 and its underlying mechanism in HCC progression. The biological behaviors of HCC cells were analyzed by cell counting kit-8 and transwell assay. The underlying mechanism was determined by quantitative real-time PCR, methylated RNA immunoprecipitation (MeRIP), RIP, and xenograft tumor experiment. The results indicated that miR-1293 was highly expressed in HCC. Upregulated miR-1293 promoted the viability, invasion, and migration of HCC cells. Mechanically, the level of METTL3 and m6A modification was increased in HCC cells. METTL3 accelerated the processing and maturation of pri-miR-1293 in an m6A-dependent manner. Moreover, miR-1293 mimic reversed the inhibitory effect of METTL3 knockdown on HCC cellular biological behaviors. In addition, miR-1293 promoted tumor growth in vivo. This study revealed the regulatory role of miR-1293 in HCC is related to the participation of METTL3-mediated m6A methylation, which could provide new therapeutic strategies for HCC.

RNA modifications, particularly N6-methyladenosine (m6A), play crucial roles in gene expression regulation. While extensively studied in the context of mRNA, the impact of m6A on long non-coding RNAs (lncRNAs) remains elusive. This research aimed to reveal the regulatory landscape of m6A in lncRNA expression. In a comprehensive analysis across 6219 samples spanning 12 cancer types, we unveiled METTL3 as the most potent regulator of lncRNA expression among the examined 19 m6A regulators. A total of 397 METTL3-mediated m6A-modified lncRNAs (mmlncRs) were unveiled across 12 cancer types, indicating a consistent mechanism of METTL3-mediated lncRNA regulation. Functional assays demonstrated that METTL3 knockout significantly impeded lung cancer cell proliferation and progression. Leveraging RNA-seq and MeRIP-seq, we identified C1RL-AS1 as a bona fide m6A target of METTL3 in lung cancer, revealing its oncogenic role. Mechanistically, METTL3 depletion disrupts m6A modification on C1RL-AS1, leading to its downregulated expression. YTHDF2 binds to C1RL-AS1, maintaining its stability in a m6A-dependent manner. This study provides a valuable resource for the exploration of mmlncRs as promising therapeutic targets in cancers, shedding light on the intricate regulatory networks orchestrated by METTL3.

The most common form of internal RNA modification in eukaryotes is called n6-methyladenosine (m6A) methylation. It has become more and more well-known as a research issue in recent years since it alters RNA metabolism and is involved in numerous biological processes. Currently, m6A alteration offers new opportunities in clinical applications and is intimately linked to carcinogenesis. Ferroptosis-a form of iron-dependent, lipid peroxidation-induced regulated cell death-was discovered. In the development of cancer, it has become an important factor. According to newly available data, ferroptosis regulates tumor growth, and cancer exhibits aberrant m6A levels in crucial ferroptosis regulatory components. On the other hand, m6A has multiple roles in the development of tumors, and the relationship between m6A-modified ferroptosis and malignancies is quite intricate. In this review, we first give a thorough review of the regulatory and functional roles of m6A methylation, focusing on the molecular processes of m6A through the regulation of ferroptosis in human cancer progression and metastasis, which are strongly associated to cancer initiation, progression, and drug resistance. Therefore, it is crucial to clarify the relationship between m6A-mediated regulation of ferroptosis in cancer progression, providing a new strategy for cancer treatment with substantial clinical implications.

This paper examined the role of solute carrier family 2 member 1 (SLC2A1) in colorectal cancer (CRC) progression, focusing on its expression levels, functional implications, and regulatory mechanisms involving Yes-associated protein 1 (YAP1) and the Wnt signaling pathway.

GEO datasets (GSE14297, GSE18462, GSE40367) were analyzed to identify genes linked to metastasis in CRC, and TCGA-COAD system was used to analyze the expression pattern and prognostic values of SLC2A1 in CRC. Functional studies were conducted using CRC cell lines (Caco-2 and SW480). Cell viability, migration and invasion, and apoptosis were examined using EdU assays, Transwell assays, and flow cytometry. YAP1's regulatory role on SLC2A1 was investigated using ChIP-qPCR and luciferase reporter assays. The Wnt/β-catenin agonist SKL2001 was used for functional rescue experiments.

SLC2A1 was upregulated in CRC cells, and its upregulation was associated with tumor metastasis and unfavorable outcomes according to bioinformatics. Knockdown of SLC2A1 resulted in reduced cell viability, decreased migration, and increased apoptosis in Caco-2 and SW480 cells. Additionally, YAP1 was identified as a transcriptional activator of SLC2A1. Knockdown of YAP1 decreased SLC2A1 expression and reduced expression of Wnt target genes, thus suppressing malignant behavior of tumor cells. However, further overexpression of SLC2A1 restored cell viability and migration in YAP1-deficient cells. The YAP1- SLC2A1 axis activated the Wnt/β-catenin by reducing GSK3β activity.

SLC2A1 is critical in CRC progression, with YAP1 serving as a key regulator of its expression and function. The YAP1-SLC2A1-Wnt axis represents a potential therapeutic target for CRC, providing insights into metabolic adaptations that support tumor growth and metastasis.

N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.

The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.

This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Pancreatic cancer is a highly malignant digestive tumor. Glutamine metabolism is one of the important sources of tumors. N6-methyladenosine (m6A) modification plays a key role in regulating tumor metabolism and holds promise as a therapeutic target in various cancers, including pancreatic cancer. Disrupting m6A regulation of glutamine metabolism could impair tumor growth, offering potential new therapeutic strategies. However, the functional role of m6A modifications in pancreatic cancer, especially in glutamine metabolism, remains poorly understood.

The Cancer Genome Atlas (TCGA) dataset and GEPIA bioinformatics tool were used to identify the relationship between m6A related proteins and the glutamine metabolism-associated genes, respectively. The biological effects of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were investigated using in vitro and in vivo models. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-PCR and RNA immunoprecipitation (RIP) were used to identify solute carrier family 1 member 5 (SLC1A5) as a direct target of IGF2BP2.

We found that IGF2BP2 expression and SLC1A5 were significantly correlated and both highly expressed in pancreatic cancer could predict poor prognosis in patients with pancreatic cancer. Functionally, silencing IGF2BP2 suppressed tumor growth and also inhibited glutamine uptake by tumor cells. Mechanistically, IGF2BP2 induced the m6A-SLC1A5-mTORC1 axis, facilitating the uptake of glutamine by pancreatic cancer cells and accelerate the progress of pancreatic cancer. Furthermore, silencing IGF2BP2 can enhance the sensitivity of pancreatic cancer to radiotherapy and chemotherapy.

Our findings suggest that IGF2BP2 promotes pancreatic cancer by activating the m6A-SLC1A5 -mTORC1 axis. Targeting the m6A machinery, particularly IGF2BP2, offers a novel therapeutic avenue for pancreatic cancer treatment. By disrupting the regulation of glutamine metabolism, we provide new insights into how m6A-based therapies could enhance the efficacy of current treatments and offer hope for improving patient outcomes in this difficult-to-treat cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, emphasizing the need for improved prognostic biomarkers. Recent studies have identified the mRNA-modifying METTL3 oncogene as a potential biomarker in CRC progression.

This study aimed to investigate the expression patterns of METTL3 in CRC, assess its association with clinical outcomes, identify interacting proteins and biological pathways, and explore its correlation with immune cell infiltration.

Comprehensive analyses were conducted using public datasets, including transcriptome profiles from The Cancer Genome Atlas and the GSE103512 dataset. Protein-protein interaction (PPI) networks, pathway enrichment, and immune infiltration analyses were performed to elucidate METTL3's role in CRC progression.

METTL3 expression was significantly higher in CRC tissues compared to normal tissues (p < 0.001). Mutations in METTL3 were detected in approximately 6% of CRC cases, with fusion events involving the SRPK2 gene. PPI analysis identified ten interacting proteins, including METTL4, EIF3H, RBM15B1, CBLL1, WTAP, NCBP1, RBM15, ZC3H13, METTL14, and KIAA1429. METTL3 expression showed a positive correlation with METTL4, METTL14, NCBP1, and WTAP expression (R > 0.5, p < 0.001). Higher METTL3 expression was associated with immunosuppressive phenotypes, such as increased infiltration of tumor-associated macrophages, regulatory T cells, and cancer-associated fibroblasts (p < 0.001). Pathway enrichment analysis revealed METTL3's involvement in crucial pathways, including the cell cycle and renal cell carcinoma (p < 0.01). Gene ontology analysis highlighted its role in mRNA and RNA-related processes.

The study supports the potential of METTL3 as a prognostic biomarker in CRC and highlights its involvement in immune modulation and cancer progression. These findings lay the groundwork for future studies aimed at developing targeted therapies and improving patient outcomes.

Dysregulation of m6A modification has emerged as a vital factor in the development of esophageal squamous cell carcinoma (ESCC). Here, we sought to explore the critical role of m6A methylation mediated by the m6A methyltransferase METTL3 in ESCC. Protein expression analysis was performed by immunohistochemistry and immunoblot assays. The mRNA levels of METTL3 and IFI27 were detected by quantitative PCR. Cell sphere formation potential, migration, invasiveness, apoptosis, proliferation and viability were assessed by standard sphere formation, wound healing, transwell, flow cytometry, EdU and CCK-8 assays, respectively. The impact of METTL3 or IGF2BP2 on IFI27 mRNA was evaluated by methylated RNA immunoprecipitation (MeRIP), RIP or mRNA stability analysis. Xenograft assays were used to detect the in vivo function of METTL3. Elevated levels of METTL3 were observed in ESCC tumors and cells, and these increased levels were associated with the declined prognosis of ESCC. MELLT3 depletion impeded ESCC cell growth, invasiveness, migration, and sphere formation, and induced cell apoptosis in vitro. Elevated IFI27 expression was positively correlated with METTL3 levels in ESCC. Moreover, METTL3 mediated m6A methylation of IFI27 mRNA to stabilize the mRNA. The m6A reader IGF2BP2 also affected m6A methylation and expression of IFI27 mRNA. Additionally, IFI27 re-expression had a counteracting impact on the effects of METTL3 deficiency on in vitro ESCC cell behaviors and in vivo KYSE30 xenograft growth. Our findings demonstrate that METTL3-mediated IFI27 mRNA m6A methylation drives ESCC development through an IGF2BP2-dependent mechanism. Blocking the METTL3/IFI27 axis may be effective for preventing ESCC.

Colorectal cancer (CRC) remains a significant clinical challenge, with 5-Fluorouracil (5-FU) being the frontline chemotherapy. However, chemoresistance remains a major obstacle to effective treatment. METTL3, a key methyltransferase involved in RNA methylation processes, has been implicated in CRC carcinogenesis. However, its role in modulating CRC sensitivity to 5-FU remains elusive. In this study, we aimed to investigate the role and mechanisms of METTL3 in regulating 5-FU chemosensitivity in CRC cells. Initially, we observed that 5-FU treatment inhibited cell viability and induced apoptosis, accompanied by a reduction in METTL3 expression in HCT-116 and HCT-8 cells. Subsequent assays including drug sensitivity, EdU, colony formation, TUNEL staining, and flow cytometry revealed that METTL3 depletion enhanced 5-FU sensitivity and increased apoptosis induction both in vitro and in vivo. Conversely, METTL3 overexpression conferred resistance to 5-FU in both cell lines. Moreover, knockdown of METTL3 in 5-FU-resistant CRC cell lines HCT-116/FU and HCT-15/FU significantly decreased 5-FU tolerance and induced apoptosis upon 5-FU treatment. Mechanistically, we found that METTL3 regulated 5-FU sensitivity and apoptosis induction by modulating TRAP1 expression. Further investigations using m6A colorimetric ELISA, dot blot, MeRIP-qPCR and RNA stability assays demonstrated that METTL3 regulated TRAP1 mRNA stability in an m6A-dependent manner. Additionally, overexpression of TRAP1 mitigated the cytotoxic effects of 5-FU on CRC cells. In summary, our study uncovers the pivotal role of the METTL3/TRAP1 axis in modulating 5-FU chemosensitivity in CRC. These findings provide new insights into the mechanisms underlying CRC resistance to 5-FU and may offer potential targets for future therapeutic interventions.

Hepatocellular carcinoma (HCC) is characterized by high incidence, significant mortality, and marked heterogeneity, making accurate molecular subtyping essential for effective treatment. Using multi-omics data from HCC patients, we applied diverse clustering algorithms to identify three HCC subtypes (HSs) with distinct prognostic characteristics. Among these, HS1 emerged as an immune-compromised subtype associated with the poorest prognosis. Additionally, we developed a novel, robust, and highly accurate machine learning-guided prognostic signature (MLPS) by integrating multiple machine learning algorithms and their combinations. Our study also identified SLC2A1, the core gene of MLPS, as being highly expressed during advanced stages of tumor progression. Knockdown experiments demonstrated that reducing SLC2A1 expression significantly suppressed the malignant behavior of HCC cells. Furthermore, SLC2A1 expression was linked to responsiveness to dasatinib and vincristine, suggesting potential therapeutic relevance. MLPS and SLC2A1 offer promising tools for individualized prognosis prediction and targeted therapy in HCC, providing new opportunities to improve patient outcomes.

Wilms tumor 1-associated protein (WTAP) plays a critical role in various cancers, including colorectal cancer (CRC). However, the biological function and molecular mechanisms of WTAP in CRC remain to be elucidated.

We determined the expression of WTAP and its correlation with unfavorable prognosis of CRC using RNA-seq and the UALCAN dataset. And we investigated the effects of WTAP on CRC cells using cell proliferation assay, colony formation, cell migration and invasion, and subcutaneous xenograft experiments. We then knockdown of WTAP to identify candidate targets of WTAP. Moreover, the mRNA stability of SRY-box transcription factor 1 (SOX1) was assessed by overexpressing YTHDF2. Finally, we investigated the regulatory mechanism of WTAP in CRC by MeRIP assay, RNA pulldown, dual-luciferase reporter assay, and RIP assay.

We demonstrated that CRC patients with a high expression of WTAP have a risk prognosis. Additionally, WTAP expression can serve as a predictor of survival in CRC. WTAP promoted the proliferation and tumor growth of CRC cells. Moreover, WTAP has been recognized as the upstream regulator of SOX1. WTAP regulated the m6A modification, resulting in the post-transcriptional inhibition of SOX1. YTHDF2 plays a role in promoting mRNA degradation. Then, SOX1 can hinder the progression of CRC. Furthermore, WTAP can regulate the proliferation, migration, and invasion of CRC cells by SOX1 via an m6A-YTHDF2-dependent manner.

Our findings demonstrate that WTAP-mediated m6A modification facilitated the progression of CRC through the YTHDF2-SOX1 axis and could serve as a potential therapeutic targeting for CRC.

Colorectal cancer (CRC) recurrence post-surgery remains a major challenge. While Chimeric Antigen Receptor (CAR)-engineered natural killer (NK) cells hold immense therapeutic potential, their intratumoral infiltration ability remains limited, hampering efficacy. Building upon prior research suggesting that chemokines like C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10) recruit CAR-NK cells, we hypothesized that tumor cell m6A methylation, regulated by Methyltransferase-like 3 (METTL3), influences chemokine secretion. This study aims to elucidate the underlying mechanisms and improve METTL3 inhibition efficiency. We designed an adhesive hemostasis hydrogel loaded with STM2457, a METTL3 inhibitor, aimed at sustained release in the acidic tumor microenvironment. In vitro, the hydrogel promoted CAR-NK cell recruitment and tumor killing via sustained METTL3 inhibition. The hydrogel's Schiff base bonds further enabled intestinal adhesion and hemostasis in an incomplete tumor resection model of CRC. Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.

RNA modifications are emerging as critical cancer regulators that influence tumorigenesis and progression. Key modifications, such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C), are implicated in various cellular processes. These modifications are regulated by proteins that write, erase, and read RNA and modulate RNA stability, splicing, translation, and degradation. Recent studies have highlighted their roles in metabolic reprogramming, signaling pathways, and cell cycle control, which are essential for tumor proliferation and survival. Despite these scientific advances, the precise mechanisms by which RNA modifications affect cancer remain inadequately understood. This review comprehensively examines the role RNA modifications play in cancer proliferation, metastasis, and programmed cell death, including apoptosis, autophagy, and ferroptosis. It explores their effects on epithelial-mesenchymal transition (EMT) and the immune microenvironment, particularly in cancer metastasis. Furthermore, RNA modifications' potential in cancer therapies, including conventional treatments, immunotherapy, and targeted therapies, is discussed. By addressing these aspects, this review aims to bridge current research gaps and underscore the therapeutic potential of targeting RNA modifications to improve cancer treatment strategies and patient outcomes.

Colorectal cancer (CRC) is the third most common cancer type and the second highest mortality rate among cancers. However, the mechanisms underlying CRC progression remain to be fully understood. In this work, a recently identified m6A-modified RNA reader protein Proline-rich Coiled-coil 2a (PRRC2A) is markedly upregulated in CRC, and intestinal epithelium-specific deletion of Prrc2a significantly suppressed tumor cell growth, stemness, and migratory capacity, while its overexpression promoted these behaviors. Through multiomics analysis, PRRC2A directly targeted CSNK1E (encoding CK1ε), maintaining its RNA stability in an m6A-dependent manner, and that elevated CK1ε can concomitantly result in activation of the WNT and YAP signaling pathways. Interestingly, PRRC2A is directly regulated by the transcription factor ATF1 in its promoter. In summary, the work reveals a novel mechanism by which m6A reader PRRC2A promotes colorectal cancer progression via CK1ε and aberrant upregulation of WNT and YAP signaling. Therefore, PRRC2A and CK1ε can be potential therapeutic targets for treating CRC.

The epigenome coordinates spatial-temporal specific gene expression during development and in adulthood, for the maintenance of homeostasis and upon tissue repair. The upheaval of the epigenetic landscape is a key event in the onset of many pathologies including tumours, where epigenetic changes cooperate with genetic aberrations to establish the neoplastic phenotype and to drive cell plasticity during its evolution. DNA methylation, histone modifiers and readers or other chromatin components are indeed often altered in cancers, such as carcinomas that develop in epithelia. Lining the surfaces and the cavities of our body and acting as a barrier from the environment, epithelia are frequently subjected to acute or chronic tissue damages, such as mechanical injuries or inflammatory episodes. These events can activate plasticity mechanisms, with a deep impact on cells' epigenome. Despite being very effective, tissue repair mechanisms are closely associated with tumour onset. Here we review the similarities between tissue repair and carcinogenesis, with a special focus on the epigenetic mechanisms activated by cells during repair and opted by carcinoma cells in multiple epithelia. Moreover, we discuss the recent findings on inflammatory and wound memory in epithelia and describe the epigenetic modifications that characterise them. Finally, as wound memory in epithelial cells promotes carcinogenesis, we highlight how it represents an early step for the establishment of field cancerization.

Ischemia-reperfusion (I/R) injury frequently occurs during liver surgery, representing a major reason for liver failure and graft dysfunction after operation. The metabolic shift from oxidative phosphorylation to glycolysis during ischemia increased glucose consumption and accelerated lactate production. We speculate that donor livers will initiate gluconeogenesis, the reverse process of glycolysis in theory, to convert noncarbohydrate carbon substrates (including lactate) to glucose to reduce the loss of hepatocellular energy and foster glycogen storage for use in the early postoperative period, thus improving post-transplant graft function.

By analyzing human liver specimens before and after hepatic I/R injury, we found that the rate-limiting enzyme of gluconeogenesis, PCK1, was significantly induced during liver I/R injury. Mouse models with liver I/R operation and hepatocytes treated with hypoxia/reoxygenation confirmed upregulation of PCK1 during I/R stimulation. Notably, high PCK1 level in human post-I/R liver specimens was closely correlated with better outcomes of liver transplantation. However, blocking gluconeogenesis with PCK1 inhibitor aggravated hepatic I/R injury by decreasing glucose level and deepening lactate accumulation, while overexpressing PCK1 did the opposite. Further mechanistic study showed that methyltransferase 3-mediated RNA N6-methyladinosine modification contributes to PCK1 upregulation during hepatic I/R injury, and hepatic-specific knockout of methyltransferase 3 deteriorates liver I/R injury through reducing the N6-methyladinosine deposition on PCK1 transcript and decreasing PCK1 mRNA export and expression level.

Our study found that activation of the methyltransferase 3/N6-methyladinosine-PCK1-gluconeogenesis axis is required to protect against hepatic I/R injury, providing potential intervention approaches for alleviating hepatic I/R injury during liver surgery.

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck squamous cell carcinoma prevalent in Southern China, Southeast Asia, and North Africa. Despite advances in treatment options, the prognosis for advanced NPC remains poor, underscoring the urgent need to explore its underlying mechanisms and develop novel therapeutic strategies. Epigenetic alterations have been shown to play a key role in NPC progression. Recent studies indicate that dysregulation of RNA modifications in NPC specifically affects tumor-related transcripts, influencing various oncogenic processes. This review provides a comprehensive overview of altered RNA modifications and their regulators in NPC, with a focus on m6A and its regulatory mechanisms. We discuss how m6A RNA modification influences gene expression and affects NPC initiation and progression at the molecular level, analyzing its impact on cancer-related biological functions. Understanding these modifications could reveal new biomarkers and therapeutic targets for NPC, offering promising directions for future research and precision medicine.

Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m6A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m6A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m6A modifications by enhancing the transcriptional expression levels of m6A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m6A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m6A alterations to impact lactate levels and subsequently affect lactylation processes.

There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.

Accumulating studies reveal that m6A RNA methylation plays a critical role in cancer pathogenesis and progression. METTL3 as a m6A methyltransferase acts as an oncogene in multiple malignancies including hepatocellular carcinoma (HCC). However, the role and underlying mechanism by which METTL3 contributes to HCC remains unclear. The association of METTL3 expression with clinicopathological characteristics and prognosis in patients with HCC was assessed by reverse transcription polymerase chain reaction, Western blot, and public TCGA dataset. MTT, colony formation, Transwell assays, and xenograft tumor models were executed to reveal the role of METTL3 in HCC. m6A dot blot, RNA immunoprecipitation (RIP), m6A methylated RIP, and Western blot assays were used to uncover the regulatory mechanism of METTL3 in HCC cells. We found that METTL3 was dramatically upregulated in HCC tissue samples and acted as an independent prognostic factor for poor survival and tumor recurrence in patients with HCC. Silencing of METTL3 repressed cell growth and invasion in vitro and in vivo, but restored expression of METTL3 boosted these effects. Mechanistical investigations revealed that METTL3 could directly interact with FMRP and harbor a positive correlation with FMRP expression. Knockdown of METTL3 reduced FMRP m6A levels as well as its mRNA and protein expression. FMRP overexpression drove cell colony formation and cell invasion and abolished METTL3 knockdown-induced antitumor effects and AKT/mTORC1 signaling inactivation. Elevated expression of FMRP could act as an independent prognostic factor for poor survival and tumor recurrence in patients with HCC. Our findings demonstrate that METTL3-mediated m6A modification of FMRP promotes growth and invasion of HCC cells and may provide a promising therapeutic target for HCC.

The 5' cap, catalyzed by RNA guanylyltransferase and 5'-phosphatase (RNGTT), is a vital mRNA modification for the functionality of mRNAs. mRNA capping occurs in the nucleus for the maturation of the functional mRNA and in the cytoplasm for fine-tuning gene expression. Given the fundamental importance of RNGTT in mRNA maturation and expression there is a need to further investigate the regulation of RNGTT. N6-methyladenosine (m6A) is one of the most abundant RNA modifications involved in the regulation of protein translation, mRNA stability, splicing, and export. We sought to investigate whether m6A could regulate the expression and activity of RNGTT. In this short report, we demonstrated that the 3'UTR of RNGTT mRNA is methylated with m6a by the m6A writer methyltransferase 3 (METTL3). Knockdown of METTL3 resulted in reduced protein expression of RNGTT. Sequencing of capped mRNAs identified an underrepresentation of ribosomal protein mRNA overlapping with 5' terminal oligopyrimidine (TOP) mRNAs, and genes are dysregulated when cytoplasmic capping is inhibited. Pathway analysis identified disruptions in the mTOR and p70S6K pathways. A reduction in RPS6 mRNA capping, protein expression, and phosphorylation was detected with METTL3 knockdown.

Inflammatory bowel disease (IBD) is a considerable threat to human health with a significant risk for colorectal cancer (CRC). However, currently, both the molecular pathogenesis and therapeutic treatment of IBD remain limited. In this report, using both systemic and intestinal epithelium-specific gene knockout mouse models, we demonstrate that FBXO22, a substrate receptor within the SKP1-Cullin 1-F-box family of E3 ubiquitin ligases, plays an inhibitory role in the Azoxymethane/Dextran Sodium Sulfate-induced colorectal inflammatory responses and CRC. FBXO22 targets the serine 2448-phosphorylated form of mammalian mechanistic target of rapamycin (pS2448-mTOR) for ubiquitin-dependent degradation. This proteolytic targeting effect is established based on multiple lines of evidence including the results of colon tissue immunoblots, analysis of cultured cells with altered abundance of FBXO22 by depletion or overexpression, comparison of protein decay rate, effects on mTOR substrates S6K1 and 4E-BP1, analysis of protein-protein interactions, phosphor-peptide binding and competition, as well as reconstituted and cellular ubiquitination. Finally, we have shown that mTOR inhibitor rapamycin (RAPA) was able to alleviate the effects of fbxo22 deletion on colorectal inflammatory response and CRC. These RAPA effects are correlated with the ability of RAPA to inhibit pS2448-mTOR, pS6K1, and p4E-BP1. Collectively, our data support a suppressive role for FBXO22 in colorectal inflammation signaling and CRC initiation by targeting pS2448-mTOR for degradation.

FAM136A promotes the progression and metastasis of various tumors. However, there are few studies on the role of FAM136A in esophageal cancer (ESCA). The TCGA, GTEx, and GEO databases are employed to analyze the expression of FAM136A in ESCA, and qPCR and TMA experiments are performed for validation. Enrichment analyzes are performed to investigate the association of FAM136A expression with immune features, m6A modification, alternative splicing, cuproptosis, and the ceRNA network via bioinformatics analysis. FAM136A is highly expressed in ESCA and correlated with lymph node metastasis and overall survival (OS). Bioinformatics analysis suggested that FAM136A may participate in the following processes to promote ESCA development and progression: 1) Promotion of mast cells infiltration to influence the ESCA immune microenvironment, 2) HNRNPC upregulation to regulate m6A modification, 3) ALYREF upregulation to increase the occurrence of retained intron (RI) events, 4) CDK5RAP1 upregulation to achieve inhibition of tumor cell apoptosis, and 5) promotion of ESCA progression through the lncRNA SNHG15/hsa-miR-29c-3p/FAM136A ceRNA network. FAM136A is a potential biomarker for ESCA diagnosis and treatment response evaluation, and the underlying mechanisms may be associated with immune infiltration, m6A modification, alternative splicing, cuproptosis, and the ceRNA regulatory network.

Breast cancer is the most common cancer type among women. Despite advanced treatment strategies, some patients still face challenges in disease control, prompting the exploration of new therapeutic approaches. N6-Methyladenosine (m6A) methylation modification regulates RNA and plays a crucial role in various tumor biological processes, closely linked to breast cancer occurrence, development, prognosis, and treatment. M6A regulators impact breast cancer progression, development, and drug resistance by modulating RNA metabolism and tumor-related pathways. Researchers have begun to understand the regulatory mechanisms of m6A methylation in breast cancer. This paper discusses the roles of m6A regulators in breast cancer progression, prognosis, and treatment, offering new perspectives for breast cancer diagnosis and treatment.

The most common epigenetic modification of messenger RNAs (mRNAs) is N6-methyladenosine (m6A), which is mainly located near the 3' untranslated region of mRNAs, near the stop codons, and within internal exons. The biological effect of m6A is dynamically modulated by methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). By controlling post-transcriptional gene expression, m6A has a significant impact on numerous biological functions, including RNA transcription, translation, splicing, transport, and degradation. Hence, m6A influences various physiological and pathological processes, such as spermatogenesis, oogenesis, embryogenesis, placental function, and human reproductive system diseases. During gametogenesis and embryogenesis, genetic material undergoes significant changes, including epigenomic modifications such as m6A. From spermatogenesis and oogenesis to the formation of an oosperm and early embryogenesis, m6A changes occur at every step. m6A abnormalities can lead to gamete abnormalities, developmental delays, impaired fertilization, and maternal-to-zygotic transition blockage. Both mice and humans with abnormal m6A modifications exhibit impaired fertility. In this review, we discuss the dynamic biological effects of m6A and its regulators on gamete and embryonic development and review the possible mechanisms of infertility caused by m6A changes. We also discuss the drugs currently used to manipulate m6A and provide prospects for the prevention and treatment of infertility at the epigenetic level.

As a research hotspot in the field of molecular biology, N6-methyladenosine (m6A) modification has made progress in the treatment of colorectal cancer (CRC), leukemia and other cancers. Numerous studies have demonstrated that the tumour microenvironment (TME) regulates the level of m6A modification in the host and activates a series of complex epigenetic signalling pathways through interactions with CRC cells, thus affecting the progression and prognosis of CRC. However, with the diversity in the composition of TME factors, this action is reciprocal and complex. Encouragingly, some studies have experimentally revealed that the intestinal flora can alter CRC cell proliferation by directly acting on m6A and thereby altering CRC cell proliferation. This review summarizes the data, supporting the idea that the intestinal flora can influence host m6A levels through pathways such as methyl donor metabolism and thus affect the progression of CRC. We also review the role of m6A modification in the diagnosis, treatment, and prognostic assessment of CRC and discuss the current status, limitations, and potential clinical value of m6A modification in this field. We propose that additional in-depth research on m6A alterations in CRC patients and their TME-related targeted therapeutic issues will lead to better therapeutic outcomes for CRC patients.

Among over 170 different types of chemical modifications on RNA nucleobases identified so far, RNA methylation is the major type of epitranscriptomic modifications existing on almost all types of RNAs, and has been demonstrated to participate in the entire process of RNA metabolism, including transcription, pre-mRNA alternative splicing and maturation, mRNA nucleus export, mRNA degradation and stabilization, mRNA translation. Attributing to the development of high-throughput detection technologies and the identification of both dynamic regulators and recognition proteins, mechanisms of RNA methylation modification in regulating the normal development of the organism as well as various disease occurrence and developmental abnormalities upon RNA methylation dysregulation have become increasingly clear. Here, we particularly focus on three types of RNA methylations: N6-methylcytosine (m6A), 5-methylcytosine (m5C), and N7-methyladenosine (m7G). We summarize the elements related to their dynamic installment and removal, specific binding proteins, and the development of high-throughput detection technologies. Then, for a comprehensive understanding of their biological significance, we also overview the latest knowledge on the underlying mechanisms and key roles of these three mRNA methylation modifications in gametogenesis, embryonic development, immune system development, as well as disease and tumor progression.

Many studies have demonstrated the relationship between METTL3 protein expression and clinical outcomes in various cancers and elucidated the mechanism by which METTL3 disrupts the behavior of cancer cells. Here, we attempted to define the prognostic value of METTL3 protein in patients with cancer via systematic analysis and explored the potential effect of inhibiting METTL3 using its specific inhibitor.

We searched PubMed, Embase, and the Web of Science databases for studies that elucidated the prognostic value of METTL3 protein expression in all cancer types and then calculated the pooled hazard ratios with 95% confidence intervals for the overall survival (OS) of all cancer types and subgroups. Data from The Cancer Genome Atlas dataset were used to study METTL3 mRNA expression in cancers. Further, the effects of a METTL3-specific inhibitor were studied in cancer cells via the colony formation assay, the cell proliferation assay, and apoptosis detection.

Meta-analysis of the 33 cohorts in 32 studies (3666 patients in total) revealed that higher METTL3 protein expression indicated poor OS in the majority of cancers. Bioinformatics analysis of METTL3 mRNA expression and cancer prognosis did not show the extremely prominent prognostic value of METTL3 mRNA. Nevertheless, the METTL3-specific inhibitor attenuated cell proliferation and cell cloning formation and promoted apoptosis.

METTL3 protein expression is associated with poor prognosis in most cancer types and could be a biomarker for OS. Further, METTL3 inhibition might be a potential treatment strategy for cancers.