m6A modification mediates SLC3A2/SLC7A5 translation in 3-methylcholanthrene-induced uroepithelial transformation

Abstract

Abstract3-Methylcholanthracene (3-MC) is one of the most carcinogenic polycyclic aromatic hydrocarbons (PAHs). Long-term exposure to PAHs has been thought of as an important factor in urothelial tumorigenesis. N6-methyladenosine (m6A) exists widely in eukaryotic organisms and regulates the expression level of specific genes by regulating mRNA stability, translation efficiency, and nuclear export efficiency. Currently, the potential molecular mechanisms that regulate m6A modification for 3-MC carcinogenesis remain unclear. Here, we profiled mRNA, m6A, translation and protein level using “-omics” methodologies, including transcriptomes, m6A profile, translatomes, and proteomics in 3-MC-transformed urothelial cells and control cells. The key molecules SLC3A2/SLC7A5 were screened and identified in 3-MC-induced uroepithelial transformation. Moreover, SLC7A5/SLC3A2 promoted uroepithelial cells malignant phenotype in vitro and in vivo. Mechanically, METTL3 and ALKBH5 mediated m6A modification of SLC3A2/SLC7A5 mRNA in 3-MC-induced uroepithelial transformation by upregulating the translation of SLC3A2/SLC7A5. Furthermore, programmable m6A modification of SLC3A2/SLC7A5 mRNA affected the expression of its proteins. Taken together, our results revealed that the m6A modification-mediated SLC3A2/SLC7A5 translation promoted 3-MC-induced uroepithelial transformation, suggesting that targeting m6A modification of SLC3A2/SLC7A5 may be a potential therapeutic strategy for bladder cancer related to PAHs.

Glioma Cells Achieve Malignant Progression by Fusion with Macrophages to Gain High SLC7A5 Expression

“…The same gene may exhibit differential behavior in cancerous cells compared to somatic cells. In tumor cells, SLC7A5 typically facilitates the proliferation and invasion of tumor cells by mediating the phosphorylation activation of mTOR protein [39,40]. Additionally, RPS6 serves as a crucial effector protein downstream of the mTOR pathway, and its phosphorylation activation also promotes cell growth and division [47].…”

“…In summary, these results demonstrate that SLC7A5 is pivotal in enhancing the proliferative and invasive properties of MФ-glioma fusion hybrids. SLC7A5 facilitates the proliferation and invasion of tumor cells by activating the mTOR pathway and its downstream signals [39,40]. We examined the activation status of mTOR and its downstream RPS6 protein in MФ-glioma fusion hybrids as well as their parental cells.…”