O-GlcNAcylation links oncogenic signals and cancer epigenetics

Abstract

Prevalent dysregulation of epigenetic modifications plays a pivotal role in cancer. Targeting epigenetic abnormality is a new strategy for cancer therapy. Understanding how conventional oncogenic factors cause epigenetic abnormality is of great basic and translational value. O-GlcNAcylation is a protein modification which affects physiology and pathophysiology. In mammals, O-GlcNAcylation is catalyzed by one single enzyme OGT and removed by one single enzyme OGA. O-GlcNAcylation is affected by the availability of the donor, UDP-GlcNAc, generated by the serial enzymatic reactions in the hexoamine biogenesis pathway (HBP). O-GlcNAcylation regulates a wide spectrum of substrates including many proteins involved in epigenetic modification. Like epigenetic modifications, abnormality of O-GlcNAcylation is also common in cancer. Studies have revealed substantial impact on HBP enzymes and OGT/OGA by oncogenic signals. In this review, we will first summarize how oncogenic signals regulate HBP enzymes, OGT and OGA in cancer. We will then integrate this knowledge with the up to date understanding how O-GlcNAcylation regulates epigenetic machinery. With this, we propose a signal axis from oncogenic signals through O-GlcNAcylation dysregulation to epigenetic abnormality in cancer. Further elucidation of this axis will not only advance our understanding of cancer biology but also provide new revenues towards cancer therapy.

Keywords: Chromatin; Epigenetics; Hexoamine biosynthesis pathway; Histone; O-GlcNAcylation; OGA; OGT.

Fig. 1

The HBP pathway and Protein O-GlcNAcylation. GFPT1/2, GNPNAT1, PGM3, UAP1 in the HBP pathway generates UDP-GlcNAc. OGT can then O-GlcNAcylate protein substrates with UDP-GlcNAc as donor. O-GlcNAcylation has pleiotropic effects on substrates and can be removed by OGA

Fig. 2

Oncogenic signal/O-GlcNAcylation/Epigenetic Modification Axis. Virus Oncoproteins and Tumor microenvironmental factor can regulate HBP enzymes and OGT/OGA directly or indirectly through intracellular oncogenic signals. Consequently, abnormality in HBP enzymes/OGT/OGA can cause abnormality in epigenetic modification in cancer