The Mutual Relationship between Glycosylation and Non-Coding RNAs in Cancer and Other Physio-Pathological Conditions

Abstract

Glycosylation, which consists of the enzymatic addition of sugars to proteins and lipids, is one of the most important post-co-synthetic modifications of these molecules, profoundly affecting their activity. Although the presence of carbohydrate chains is crucial for fine-tuning the interactions between cells and molecules, glycosylation is an intrinsically stochastic process regulated by the relative abundance of biosynthetic (glycosyltransferases) and catabolic (glycosidases) enzymes, as well as sugar carriers and other molecules. Non-coding RNAs, which include microRNAs, long non-coding RNAs and circRNAs, establish a complex network of reciprocally interacting molecules whose final goal is the regulation of mRNA expression. Likewise, these interactions are stochastically regulated by ncRNA abundance. Thus, while protein sequence is deterministically dictated by the DNA/RNA/protein axis, protein abundance and activity are regulated by two stochastic processes acting, respectively, before and after the biosynthesis of the protein axis. Consequently, the worlds of glycosylation and ncRNA are closely interconnected and mutually interacting. In this paper, we will extensively review the many faces of the ncRNA-glycosylation interplay in cancer and other physio-pathological conditions.

Keywords: glycosylation; glycosyltransferases; miRNA; non-coding RNAs; sugar antigens.

Figure 1

LncRNAs and circRNAs. Gene A comprises 4 exons (in green, red, yellow and blue, respectively). Its promoter is depicted in violet. Intergenic lncRNAs are generated by transcription of sequences between genes; intronic lncRNAs are generated by transcription of intronic regions between exons of a coding gene; antisense lncRNAs are produced by transcription of the antisense DNA strand; bidirectional lncRNAs are produced from the antisense transcription starting from the promoter of the coding gene; enhancer RNAs are derived from enhancer sequences; pseudogene lncRNAs are produced by transcription of genes carrying inactivating mutations (pseudogenes). Mutation is marked by an asterisk. circRNAs are produced from (left to right) intronic sequences, single exons, multiple exons and intronic and exonic sequences.

Figure 2

N-glycosylation steps regulated by ncRNAs. Black arrows indicate single-step reactions. White arrows indicate that the indicated transition is the product of multiple steps.

Figure 3

Pathways of O-glycosylation. (A) mucin-type; (B) O-GlcNAc. Enzymes catalyzing the same reactions but not mentioned in the text are not shown.

Figure 4

Pathways of glycolipid biosynthesis. Black arrows indicate single-step reactions. White arrows indicate that the indicated transition is the product of multiple steps. Enzymes catalyzing the same reactions but not mentioned in the text are not shown.

Figure 5

Elongating (A) and capping (B) glycosyltransferases. Enzymes catalyzing the same reactions but not mentioned in the text are not shown.

Figure 6

Glycogenes modulated by ncRNAs in different cancer types. Only cancers with at least 3 modulated glycogenes are reported. MiRNAs modulating different enzymes in the same cancer type are boxed.