3-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. N 6 -methyladenosine (m 6 A) 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 m 6 A modification for 3-MC carcinogenesis remain unclear. Here, we profiled mRNA, m 6 A, translation and protein level using "-omics" methodologies, including transcriptomes, m 6 A 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 m 6 A modification of SLC3A2/SLC7A5 mRNA in 3-MC-induced uroepithelial transformation by upregulating the translation of SLC3A2/SLC7A5. Furthermore, programmable m 6 A modification of SLC3A2/SLC7A5 mRNA affected the expression of its proteins. Taken together, our results revealed that the m 6 A modification-mediated SLC3A2/SLC7A5 translation promoted 3-MC-induced uroepithelial transformation, suggesting that targeting m 6 A modification of SLC3A2/SLC7A5 may be a potential therapeutic strategy for bladder cancer related to PAHs.
Keyphrases
- polycyclic aromatic hydrocarbons
- induced apoptosis
- high glucose
- diabetic rats
- binding protein
- cell cycle arrest
- heavy metals
- poor prognosis
- single cell
- gene expression
- endothelial cells
- high grade
- health risk assessment
- endoplasmic reticulum stress
- genome wide
- signaling pathway
- multidrug resistant
- dna methylation
- drug delivery
- drinking water
- climate change
- protein protein
- cancer therapy
- bioinformatics analysis