Hexosamine Signaling Regulates Cancer Stem Cell Properties: Significance of Hyaluronan Production and Protein <i>O</i>-GlcNAcylation

Abstract

Hyaluronan (HA) is a major glycosaminoglycan in the extracellular matrix and is also seen in the tumor microenvironment. HA-rich matrix is widely observed in tumor tissues and is strongly related to the malignancy potential. HA production was closely associated with the regulation of cancer stem cells (CSCs). CSCs are a stem cell-like subpopulation of cancer cells and are considered to be responsible for tumor initiation, growth, and recurrence. Recent findings suggested that the regulation of CSC properties strongly depends on cancer metabolism. HA production markedly induces the reprogramming of glucose metabolism, including the hexosamine biosynthetic pathway (HBP). The end product of HBP is a nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc) which is utilized as a substrate for HA and glycosaminoglycans synthesis as well as for O-linked N-acetylglucosamine (O-GlcNAc) modification of proteins. Protein O-GlcNAcylation is another essential factor for the regulation of CSC properties. In this minireview, I outline the significance of HA production and O-GlcNAcylation in CSC regulation.