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Abstract
In this review, the sugar portions of glycoproteins, glycolipids, and glycosaminoglycans constitute the glycome, and the genes involved in their biosynthesis, degradation, transport and recognition are referred to as “glycogenes“. The extreme complexity of the glycome requires the regulatory layer to be provided by the epigenetic mechanisms. Almost all types of cancers present glycosylation aberrations, giving rise to phenotypic changes and to the expression of tumor markers. In this review, we discuss how cancer-associated alterations of promoter methylation, histone methylation/acetylation, and miRNAs determine glycomic changes associated with the malignant phenotype. Usually, increased promoter methylation and miRNA expression induce glycogene silencing. However, treatment with demethylating agents sometimes results in silencing, rather than in a reactivation of glycogenes, suggesting the involvement of distant methylation-dependent regulatory elements. From a therapeutic perspective aimed at the normalization of the malignant glycome, it appears that miRNA targeting of cancer-deranged glycogenes can be a more specific and promising approach than the use of drugs, which broad target methylation/acetylation. A very specific type of glycosylation, the addition of GlcNAc to serine or threonine (O-GlcNAc), is not only regulated by epigenetic mechanisms, but is an epigenetic modifier of histones and transcription factors. Thus, glycosylation is both under the control of epigenetic mechanisms and is an integral part of the epigenetic code.
Highlights
As a part of the genome, genes involved in the biosynthesis, degradation, transport, and recognition of the sugar portions of glycoconjugates undergo epigenetic regulation
It has been hypothesized that the epigenetic regulation of glycogenes provides mammalians with a quick and heritable mechanism generating glycome plasticity to cope with microorganisms [1,2]
We summarize the case of O-linked GlcNAc, in which glycosylation is the target of epigenetic mechanisms, but contributes to the generation of the epigenetic code
Summary
As a part of the genome, genes involved in the biosynthesis, degradation, transport, and recognition of the sugar portions of glycoconjugates (collectively referred to as glycogenes) undergo epigenetic regulation. Since glycans are not primary gene products, but secondary products of a complex interplay among glycogenes, the epigenetic regulation of the glycome moves a step forward to understanding the complexity and opportunity of biological regulation. As a consequence of epigenetic regulation of glycogenes in solid tissues, the whole glycome of plasma proteins can be modulated. This leads to important functional changes, as well as to the appearance of disease-related glycomic markers [3,4,5]. We expect that the relatively small number of glycogenes epigenetically modulated in cancer so far identified are only a minority of those undergoing epigenetic regulation
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