Methylation multiplicity and its clinical values in cancer

Abstract

Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological activities and human diseases. To aid in the diagnostic and therapeutic design for cancer treatment utilising methylation, this review provides a boutique yet comprehensive overview on methylation at different levels including the mechanisms, cross-talking and clinical implications with a particular focus on cancers. We conclude that DNA methylation is the sole type of methylation that has been largely translated into clinics and used for, mostly, early diagnosis. Translating the onco-therapeutic and prognostic values of RNA and protein methylations into clinical use deserves intensive efforts. Simultaneous examination of methylations at multiple levels or together with other forms of molecular markers represents an interesting research direction with profound clinical translational potential.

Keywords: Cancer; DNA methylation; RNA methylation; early diagnosis; protein methylation.

Fig. 1.

The primary type and mechanism of DNA methylation. DNA methylation typically occurs as 5mC, with DNMT1 being the key methyltransferase (writer) and the TET family proteins playing the primary demethylation (eraser) role. Three kinds of DNA methylation-binding proteins (reader) were reported, which are MBD (Methyl-CpG-Binding Domain), Kaiso and SRA (Set and Ring Finger-associated) families. Readers identify methylated DNA sites to enable the downstream effects including, for example, gene expression suppression and genomic methylation maintenance.

Fig. 2.

The primary types and mechanisms of RNA methylation. The most representative RNA methylations are m6A and m5C. (a) In m6A RNA methylation, m6A is catalysed by the METTL3/METTL14/WTAP methyltransferase complex (m6A writer) and removed by FTO and ALKBH5 (m6A eraser). In addition, YTHDC1, YTHDC2 and YTHDF1 to YTHDF3 are m6A methylation-dependent binding proteins (m6A reader) to enable functionalities such as regulating mRNA splicing, enhance translation and mediate mRNA degradation. (b) In m5C RNA methylation, m5C is methylated by NSUN family proteins and DNMT family members as represented by DNMT2 (m5C writer) with the demethylases (m5C eraser) being unclear. ALYREF is so far the only recognised m5C methylation-dependent binding protein (m5C reader) that functions in availing mRNA nucleus export.

Fig. 3.

The primary types and mechanisms of protein methylation. Protein methylation can occur on both histone and non-histone proteins, and typically at arginine and lysine. (a) Arginine methylation is triggered by PRMT (Arg methylation writer). Some members of the JmjC family such as KDM3A, KDM4E, KDM5C (Arg methylation eraser) are known to catalyse arginine demethylation. The Tudor domain and PHD zinc finger domain recognise arginine methylation (Arg methylation reader) to play diverse roles in many cellular processes. (b) Lysine methylation is mediated by lysine methyltransferase, abbreviated as KMT (Lys methylation writer). JmjC family members and LSD1 are the primary demethylases unveiled for lysine demethylation. The ‘royal’ domain superfamily, comprised of Tudor, chromo, MBT and PWWP domains, and PHD zinc finger domain are lysine methylation readers.