Significant epitranscriptomes in heterogeneous cancer

Abstract

Precision medicine places significant emphasis on techniques for the identification of DNA mutations and gene expression by deep sequencing of gene panels to obtain medical data. However, other diverse information that is not easily readable using bioinformatics, including RNA modifications, has emerged as a novel diagnostic and innovative therapy owing to its multifunctional aspects. It is suggested that this breakthrough innovation might open new avenues for the elucidation of uncharacterized cancer cellular functions to develop more precise medical applications. The functional characteristics and regulatory mechanisms of RNA modifications, ie, the epitranscriptome (ETR), which reflects RNA metabolism, remains unclear, mainly due to detection methods being limited. Recent studies have revealed that N6‐methyl adenosine, the most common modification in mRNA in eukaryotes, is affected in various types of cancer and, in some cases, cancer stem cells, but also affects cellular responses to viral infections. The ETR can control cancer cell fate through mRNA splicing, stability, nuclear export, and translation. Here we report on the recent progress of ETR detection methods, and biological findings regarding the significance of ETR in cancer precision medicine.

Impact of One-Carbon Metabolism-Driving Epitranscriptome as a Therapeutic Target for Gastrointestinal Cancer

“…Moreover, the function of RNA modification can be exerted via "reading" enzymes, such as the protein family of heterogeneous nuclear ribonucleoproteins (hnRNP) and YT521-B homology (YTH) m6A RNA binding protein 1 (YTHDF1). Those reading enzymes recognize the methylation of RNAs and bind to different proteins, which finally affect the translation efficiency and lifetime of RNA [14].…”

“…Recent studies revealed the function of RNA modifications through the mechanisms of control of splicing, stability of transcripts, and translation process of encoded peptides [ 14 ]. Given that m6A, i.e., N6-methyl adenosine, is a predominant modification of RNA, previous studies demonstrated that the methylation reaction occurs according to consensus sequence, typically GGACU; more precisely, RRm6ACH (R notes G or A; H includes A, C, or U), or Pu (G > A) m6AC (A/C/U) (where Pu represents purine), though there are some exceptions (reviewed in [ 14 ]). The RNA modification is regulated finely by the methylation “writing” enzymes, as a forward reaction, such as Mettl3, which contains a catalytic domain, in the protein complex with Mettl14 and Wilms’ tumor 1-associating protein (Wtap) as subunits [ 14 ].…”

“…Additionally, Mettl3 constitutes the catalytic site in the heterodimer formed with Mettl14. Accordingly, m6A in the 5′-[A/G]GAC-3′ consensus sequence of mRNA plays a role in the function, such as stability, processing, translation efficiency, and editing [ 14 ]. Considering that m6A modification of RNA is involved in the circadian clock, differentiation of embryonic stem cells and hematopoietic cell lineages, cortical neurogenesis, DNA damage response, T-cell homeostasis and differentiation, and primary miRNA processing, the epitranscriptome plays a role in the heterogeneity of tumors [ 14 ].…”

“…The RNA methylation reaction can be activated through cooperative binding to the Mettl4–Mettl14–Wtap active binding site by a small molecule [ 12 ], suggesting the druggability of this RNA methylation mechanism. These data suggest the importance of the epitranscriptome in cancer [ 13 , 14 ]. In this paper, we present an update of recent advances in the study of cancer 1C metabolism, with a focus on the epitranscriptome.…”

Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes

“…Epigenetic information contained in DNA exclusively includes the methylation of cytosine at the 5′ position (5mC), which exerts the control function of the downstream gene expression in the promoter and enhancer levels [ 98 ]. Nevertheless, epigenetic information in RNA was elusive until state-of-the-art technology was developed to measure the precise position in the sequence and actual modifications [ 99 ]. The application of modified mass spectrometry analysis allowed the identification of methylation information of miRNAs, suggesting its usefulness in biomarker screening in the early phases of pancreatic cancer [ 100 ].…”