N6-methyladenosine (m6A) methylation is an abundant modification in eukaryotic mRNAs. Accumulating evidence suggests a role for RNA m6A methylation in various aspects of cancer biology. In this study, we aimed to explore the biological role of RNA m6A modification in tumor metastasis and to identify novel therapeutic strategies for esophageal squamous cell carcinoma (ESCC). Integration of genome-wide CRISPR/Cas9 functional screening with highly invasive and metastatic ESCC subline models led to the identification of METTL3, the catalytic subunit of the N6-adenosine-methyltransferase complex, as a promoter of cancer metastasis. METTL3 expression was upregulated in ESCC tumors and metastatic tissues. In vitro and in vivo experiments indicated that METTL3 increased m6A in EGR1 mRNA and enhanced its stability in a YTHDF3-dependent manner, activating EGR1/Snail signaling. Investigation into regulation of METTL3 expression found that KAT2A increased H3K27 acetylation levels in the METTL3 promoter region and activated transcription of METTL3 while SIRT2 exerted the opposite effects. Molecular docking and computational screening in a Food and Drug Administration (FDA)-approved compound library consisting of 1,443 small molecules identified compounds targeting METTL3 to suppress cancer metastasis. Elvitegravir, originally developed to treat human immunodeficiency virus (HIV) infection, suppressed metastasis by directly targeting METTL3 and enhancing its STUB1-mediated proteasomal degradation. Overall, RNA m6A modifications are important in cancer metastasis, and targeting METTL3 with elvitegravir has therapeutic potential for treating ESCC.
With the development of proteomics and epigenetics, a large number of RNAbinding proteins (RBPs) have been discovered in recent years, and the interaction between long non-coding RNAs (lncRNAs) and RBPs has also received increasing attention. It is extremely important to conduct in-depth research on the lncRNA-RBP interaction network, especially in the context of its role in the occurrence and development of cancer. Increasing evidence has demonstrated that lncRNA-RBP interactions play a vital role in cancer progression; therefore, targeting these interactions could provide new insights for cancer drug discovery. In this review, we discussed how lncRNAs can interact with RBPs to regulate their localization, modification, stability, and activity and discussed the effects of RBPs on the stability, transport, transcription, and localization of lncRNAs. Moreover, we explored the regulation and influence of these interactions on lncRNAs, RBPs, and downstream pathways that are related to cancer development, such as N6-methyladenosine (m6A) modification of lncRNAs.In addition, we discussed how the lncRNA-RBP interaction network regulates cancer cell phenotypes, such as proliferation, apoptosis, metastasis, drug resistance, immunity, tumor environment, and metabolism. Furthermore, we summarized the therapeutic strategies that target the lncRNA-RBP interaction network. Although these treatments are still in the experimental stage and various theories and processes are still being studied, we believe that these strategies may provide new ideas for cancer treatment.
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herb Glycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.
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