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.

Metabolite-derived protein modifications modulating oncogenic signaling

“…Moreover, oncoprotein YAP is stabilized by O-GlcNAcylation in both in vitro and in vivo models to promote high glucose-induced liver tumorigenesis ( 120 ). Similar, to other PTMs, oncogenes themselves can induce O-GlcNAcylation and OGT expression directly as part of their oncogenic signaling, indicating the existence of a bi-directional feedback loop between glycosylation and oncogenic expression ( 124 ).…”

The Hexosamine Biosynthesis Pathway: Regulation and Function

“…Furthermore, proteins involved in the epithelial–mesenchymal transition (EMT) and the extracellular matrix (ECM) undergo deregulated O -GlcNAcylation to promote tumor cell motility, invasion, and metastasis [ 181 , 189 ]. OGT and OGA also interact with epigenetic regulators, histones, and histone-remodeling complexes and could thereby alter the expression of genes involved in tumorigenesis and cancer progression [ 190 , 191 ]. For instance, O -GlcNAcylation epigenetically regulates the expression of the proto-oncogene MYBL1, which reduces colon cancer stem cell and tumor growth.…”

BAP1 in cancer: epigenetic stability and genome integrity

“…Epigenetic modifications as DNA methylation and histone posttranslational modifications (PTMs) regulate cellular processes. Epigenetic perturbations or even mutations in epigenetic enzymes can trigger changes in chromatin conformation leading to aberrant transcriptome which may support tumorigenesis [4][5][6]. The balance between euchromatin and heterochromatin is finely tuned by a number of chromatin modifying factors, including the Polycomb group (PcG) family, broadly classified into 3 complexes: Polycomb Repressive Complex 1 (PRC1), Polycomb Repressive Complex 2 (PRC2) and Polycomb Repressive Deubiquitinase Complex (PR-DUB) [7].…”