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Triple‐negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both in vivo and in vitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis‐related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1‐m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis. Using bioinformatics and in vivo and in vitro experiments, we identified that the YTHDC1‐dependent m6A/FOXM1/CENPA axis is involved in the regulation of glycolysis and the progression of TNBC. This discovery provides new insight into the molecular interactions driving TNBC and potential therapeutic targets for combating this aggressive cancer.

Osimertinib resistance remains a significant challenge in the treatment of non‐small cell lung cancer (NSCLC). N6‐methyladenosine (m6A) modifications are closely linked to various mechanisms of anticancer resistance and autophagy, offering new avenues for targeted therapies. However, the role of m6A‐mediated autophagy in osimertinib‐resistant NSCLC is still unclear. In this study, we utilized multi‐omics sequencing analysis and found that overexpression of the m6A methyltransferase METTL3 contributes to osimertinib resistance in NSCLC. Importantly, we identified that METTL3 positively regulates the expression of the autophagy‐related gene ubiquinone‐cytochrome C reductase complex assembly factor 2 (UQCC2) through an m6A‐dependent mechanism. Further, we confirmed that METTL3 knockdown leads to UQCC2 downregulation and triggers autophagy activation. Interestingly, lomitapide, a cholesterol‐lowering drug, was repurposed to enhance the sensitivity of cancer cells to therapy by inhibiting METTL3, which in turn activated autophagy‐associated cell death pathways, reversing osimertinib resistance. This study emphasizes the critical role of the METTL3/UQCC2 axis in autophagy‐mediated drug resistance and positions lomitapide as a promising METTL3 inhibitor and autophagy inducer with potential therapeutic effects, either alone or in combination with other anticancer agents, in patients with osimertinib‐resistant NSCLC. 1. Lomitapide can significantly inhibit the methyltransferase activity of METTL3 and reduce the m6A modification and expression of UQCC2. 2. The METTL3/UQCC2 axis inhibition by lomitapide could activate autophagy‐mediated cell death, thus reversing osimertinib resistance in NSCLC cells.

N 6 -methyladenosine (m 6 A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m 6 A often affects oncogenic and tumor-suppressing networks, m 6 A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m 6 A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m 6 A modifications intrinsically affect immune cells and how alterations in tumor cell m 6 A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m 6 A regulators with immune checkpoint blockers; generating an effective programmable m 6 A gene-editing system that enables efficient manipulation of individual m 6 A sites; establishing an effective m 6 A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m 6 A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m 6 A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.

Background YAP activation is crucial for cancer development including colorectal cancer (CRC). Nevertheless, it remains unclear whether N6-Methyladenosine (m 6 A) modified transcripts of long noncoding RNAs (lncRNAs) can regulate YAP activation in cancer progression. We investigated the functional link between lncRNAs and the m 6 A modification in YAP signaling and CRC progression. Methods YAP interacting lncRNAs were screened by RIP-sequencing, RNA FISH and immunofluorescence co-staining assays. Interaction between YAP and lncRNA GAS5 was studied by biochemical methods. MeRIP-sequencing combined with lncRNA-sequencing were used to identify the m 6 A modified targets of YTHDF3 in CRC. Gain-of-function and Loss-of-function analysis were performed to measure the function of GAS5-YAP-YTHDF3 axis in CRC progression in vitro and in vivo. Results GAS5 directly interacts with WW domain of YAP to facilitate translocation of endogenous YAP from the nucleus to the cytoplasm and promotes phosphorylation and subsequently ubiquitin-mediated degradation of YAP to inhibit CRC progression in vitro and in vivo. Notably, we demonstrate the m 6 A reader YTHDF3 not only a novel target of YAP but also a key player in YAP signaling by facilitating m 6 A-modified lncRNA GAS5 degradation, which profile a new insight into CRC progression. Clinically, lncRNA GAS5 expressions is negatively correlated with YAP and YTHDF3 protein levels in tumors from CRC patients. Conclusions Our study uncovers a negative functional loop of lncRNA GAS5-YAP-YTHDF3 axis, and identifies a new mechanism for m 6 A-induced decay of GAS5 on YAP signaling in progression of CRC which may offer a promising approach for CRC treatment.

Renal cell carcinoma (RCC) is the most common type of primary renal parenchymal malignancy in adults, with a high degree of malignancy and poor prognosis. Human renal cancer stem cells (HuRCSCs) are reported to be the main cause of drug resistance, metastasis, recurrence, and poor prognosis. Erianin is a low molecular-weight bibenzyl natural product extracted from , which inhibits the and activity of a variety of cancer cells. However, the molecular mechanisms of Erianin's therapeutic effect on HuRCSCs are unknown. Here, we isolated CD44+/CD105+ HuRCSCs from patients with renal cell carcinoma. The experiments confirmed that Erianin significantly inhibited the proliferation, invasion, angiogenesis, and tumorigenesis of HuRCSCs, and induced oxidative stress injury and Fe accumulation. qRT-PCR and western blotting showed that Erianin significantly reduced the expression levels of cellular Ferroptosis protective factors, and upregulated the expression of METTL3 and downregulated that of FTO. Dot blotting results indicated that Erianin significantly upregulated the mRNA N6-methyladenosine (m6A) modification of HuRCSCs. The results of RNA immunoprecipitation-PCR also indicated that Erianin significantly enhanced the m6A modification level of the 3' untranslated region of and mRNA in HuRCSCs, resulting in increased stability, prolonged half-life, and improved translation activity. In addition, clinical data analysis showed that the expression of correlated negatively with adverse events in patient with renal cell carcinoma. Thus, this study suggested that Erianin can induce Ferroptosis in renal cancer stem cells by promoting N6-methyladenosine modification of / mRNA, ultimately achieving a therapeutic effect on renal cancer.

Background Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N 6 -methyladenosine (m 6 A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m 6 A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m 6 A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Methods Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m 6 A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC. Results A strong correlation between METTL3 and 18 F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2 , and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M 6 A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m 6 A reader IGF2BP2 or IGF2BP2/3, respectively. Conclusions METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m 6 A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.

N6-methyladenosine (m6A) methylation, one of the most common RNA modifications, has been reported to execute important functions that affect normal life activities and diseases. Most studies have suggested that m6A modification can affect the complexity of cancer progression by regulating biological functions related to cancer. M6A modification of noncoding RNAs regulates the cleavage, transport, stability, and degradation of noncoding RNAs themselves. It also regulates cell proliferation and metastasis, stem cell differentiation, and homeostasis in cancer by affecting the biological function of cells. Interestingly, noncoding RNAs also play significant roles in regulating these m6A modifications. Additionally, it is becoming increasingly clear that m6A and noncoding RNAs potentially contribute to the clinical application of cancer treatment. In this review, we summarize the effect of the interactions between m6A modifications and noncoding RNAs on the biological functions involved in cancer progression. In particular, we discuss the role of m6A and noncoding RNAs as possible potential biomarkers and therapeutic targets in the treatment of cancers.

The transcription factor forkhead box protein O1 (FoxO1) is closely related to the occurrence and development of ovarian cancer (OC), however its role and molecular mechanisms remain unclear. Herein, we found that FoxO1 was highly expressed in clinical samples of OC patients and was significantly correlated with poor prognosis. FoxO1 knockdown inhibited the proliferation of OC cells in vitro and in vivo. ChIP‐seq combined with GEPIA2 and Kaplan–Meier database analysis showed that structural maintenance of chromosome 4 (SMC4) is a downstream target of FoxO1, and FoxO1 promotes SMC4 transcription by binding to its −1400/−1390 bp promoter. The high expression of SMC4 significantly blocked the tumor inhibition effect of FoxO1 knockdown. Furtherly, FoxO1 increased SMC4 mRNA abundance by transcriptionally activating methyltransferase‐like 14 (METTL14) and increasing SMC4 m6A methylation on its coding sequence region. The Cancer Genome Atlas dataset analysis confirmed a significant positive correlation between FoxO1, SMC4, and METTL14 expression in OC. In summary, this study revealed the molecular mechanisms of FoxO1 regulating SMC4 and established a clinical link between the expression of FoxO1/METTL14/SMC4 in the occurrence of OC, thus providing a potential diagnostic target and therapeutic strategy. FoxO1, which is overexpressed in OC, is closely related to poor clinical outcomes. FoxO1 transcriptionally activates SMC4 and promotes OC progression. FoxO1 promotes SMC4 mRNA stability via METTL14‐mediated m6A modification.

N6-methyladenosine (m 6 A) is the most prevalent and internal modification of eukaryotic mRNA. Multiple m 6 A methylation sites have been identified in the viral RNA genome and transcripts of DNA viruses in recent years. m 6 A modification is involved in all the phases of RNA metabolism, including RNA stability, splicing, nuclear exporting, RNA folding, translational modulation, and RNA degradation. Three protein groups, methyltransferases (m 6 A-writers), demethylases (m 6 A-erasers), and m 6 A-binding proteins (m 6 A-readers) regulate this dynamic reversible process. Here, we have reviewed the role of m 6 A modification dictating viral replication, morphogenesis, life cycle, and its contribution to disease progression. A better understanding of the m 6 A methylation process during viral pathogenesis is required to reveal novel approaches to combat the virus-associated diseases.

RNA demethylase ALKBH5 takes part in the modulation of N 6 -methyladenosine (m 6 A) modification and controls various cell processes. ALKBH5-mediated m 6 A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m 6 A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.