Metastasis leads to the vast majority of breast cancer mortality. Increasing evidence has shown that N6-methyladenosine (m6A) modification and its associated regulators play a pivotal role in breast cancer metastasis. Here, we showed that overexpression of the m6A reader IGF2BP1 was clinically correlated with metastasis in breast cancer patients. Moreover, IGF2BP1 promoted distant metastasis in vitro and in vivo. Mechanistically, we first identified USP10 as the IGF2BP1 deubiquitinase. USP10 can bind to, deubiquitinate, and stabilize IGF2BP1, resulting in its higher expression level in breast cancer. Furthermore, by MeRIP-seq and experimental verification, we found that IGF2BP1 directly recognized and bound to the m6A sites on CPT1A mRNA and enhanced its stability, which ultimately mediated IGF2BP1-induced breast cancer metastasis. In clinical samples, USP10 levels correlated with IGF2BP1 and CPT1A levels, and breast cancer patients with high levels of USP10, IGF2BP1, and CPT1A had the worst outcome. Therefore, these findings suggest that the USP10/IGF2BP1/CPT1A axis facilitates breast cancer metastasis, and this axis may be a promising prognostic biomarker and therapeutic target for breast cancer.

Gastrointestinal cancer, the most common solid tumor, has a poor prognosis. With the development of high-throughput sequencing and detection technology, recent studies have suggested that many chemical modifications of human RNA are involved in the development of human diseases, including cancer. m⁶A, the most abundant modification, was revealed to participate in a series of aspects of cancer progression. Recent evidence has shown that methyltransferase-like 3 (METTL3), the first identified and a critical methyltransferase, catalyzes m⁶A methylation on mRNA or non-coding RNA in mammals, affecting RNA metabolism. Abnormal m⁶A levels caused by METTL3 have been reported to be involved in different aspects of cancer development, including proliferation, apoptosis, and metastasis. In this review, we will shed light on recent findings regarding the biological function of METTL3 in gastrointestinal cancer and discuss future research directions and potential clinical applications of METTL3 for gastrointestinal cancer.

N6-methyladenosine (m⁶A) modification is the most abundant modification on eukaryotic RNA. In recent years, lots of studies have reported that m⁶A modification and m⁶A RNA methylation regulators were involved in cancer progression. However, the m⁶A level and its regulators in esophageal cancer (ESCA) remain poorly understood. In this study, we analyzed the expression of m⁶A regulators using The Cancer Genome Atlas data and found 14 of 19 m⁶A regulators are significantly increased in ESCA samples. Then we performed a univariate Cox regression analysis and LASSO (least absolute shrinkage and selection operator) Cox regression model to investigate the prognostic role of m⁶A regulators in ESCA, and the results indicated that a two-gene prognostic signature including ALKBH5 and HNRNPA2B1 could predict overall survival of ESCA patients. Moreover, HNRNPA2B1 is higher expressed in high-risk scores subtype of ESCA, indicating that HNRNPA2B1 may be involved in ESCA development. Subsequently, we confirmed that the level of m⁶A and HNRNPA2B1 was significantly increased in ESCA. We also found that HNRNPA2B1 expression positively correlated with tumor diameter and lymphatic metastasis of ESCA. Moreover, functional study showed that knockdown of HNRNPA2B1 inhibited the proliferation, migration, and invasion of ESCA. Mechanistically, we found that knockdown of HNRNPA2B1 inhibited the expression of de novo fatty acid synthetic enzymes, ACLY and ACC1, and subsequently suppressed cellular lipid accumulation. In conclusion, our study provides critical clues to understand the role of m⁶A and its regulators in ESCA. Moreover, HNRNPA2B1 functions as an oncogenic factor in promoting ESCA progression via up-regulation of fatty acid synthesis enzymes ACLY and ACC1, and it may be a promising prognostic biomarker and therapeutic target for human ESCA.

Objective: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). Design: scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. Results: Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5 ⁺ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5 ⁺ stem cells during EGCA malignant progression. Conclusion: Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT ⁺ /AQP5 ⁺ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

Tumor initiation, progression, and response to therapies depend to a great extent on interactions between malignant cells and the tumor microenvironment (TME), which denotes the cancerous/non-cancerous cells, cytokines, chemokines, and various other factors around tumors. Cancer cells as well as stroma cells can not only obtain adaption to the TME but also sculpt their microenvironment through a series of signaling pathways. The post-translational modification (PTM) of eukaryotic cells by small ubiquitin-related modifier (SUMO) proteins is now recognized as a key flexible pathway. Proteins involved in tumorigenesis guiding several biological processes including chromatin organization, DNA repair, transcription, protein trafficking, and signal conduction rely on SUMOylation. The purpose of this review is to explore the role that SUMOylation plays in the TME formation and reprogramming, emphasize the importance of targeting SUMOylation to intervene in the TME and discuss the potential of SUMOylation inhibitors (SUMOi) in ameliorating tumor prognosis.