Therapy-induced mRNA, rRNA and tRNA methylation alterations confer tolerance phenotype in tumor cells: mechanism and implications.

Drug tolerant persister cells (DTPs) refer to a transient drug-tolerance sub-population of cancer cells characteristics of phenotype plasticity and heterogeneity. This adaptive cell state is a critical transitional phase, standing on the crossroad that cancer cells reacquire drug sensitivity or enter into the permanent drug resistance. Emerging evidences indicate the epitranscriptomic regulations, particularly RNA methylations are the important mechanism underline post-transcriptional regulations of genes expression across all RNA species. RNA is integral to gene expression as messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA), which play roles in transmitting information from DNA to the synthesis of functional proteins. Methylation modifications on these RNAs are prevalent and represent a well-recognized non-genetic mechanism, exerting multifaceted regulatory effects on nucleic acid metabolism, such as nucleotide precursor availability, RNA processing dynamics, sub-cellular localization, transcript stability and translational fidelity/ efficiency. This review systematically sorts out the relevant references, demonstrating recent advances on the knowledge of the patterns of methylation modifications on mRNA, tRNA and rRNA, and how these modifications drive the generation and development of DTPs, which hallmarks of epithelial-mesenchymal transition, metabolism shift and immune escape. And then clinical strategies are delineated, leveraging pharmacological modulators of RNA-modifying enzymes alongside non-pharmaceutical lifestyle advice, for the development of therapy strategies preventing DTPs-rooted tumor relapse in this anti-tumor armamentarium with cytotoxic reagents, targeted therapies and immunotherapies.