OGT as a metabolic-epigenetic integrator in cancer: context-dependent mechanisms and therapeutic vulnerabilities

Accumulating evidence shows that specific dietary elements and metabolic conditions significantly regulate gene expression through epigenetic processes. These observations link the etiology of metabolic disorders and cancer to nutrient-dependent epigenetic reprogramming. In this context, O-GlcNAc transferase (OGT) functions as a context-dependent nutrient sensor and metabolic-epigenetic integrator.

This enzyme participates in the "histone code" by regulating gene expression and modulating chromatin remodeling. In Drosophila melanogaster, OGT is a bona fide Polycomb group (PcG) protein; however, in mammals it functions as a context-dependent, non-canonical modulator of PRC2 activity rather than a canonical PcG member. OGT interacts with Ten-Eleven Translocation (TET) family proteins, which are involved in DNA hydroxylation. This suggests that O-GlcNAcylation serves as a critical bridge between dietary influences and epigenetic regulation. Evidence from animal models supports a significant role for OGT in polycomb-dependent gene silencing. Notably, OGT modifies all core histones and may constitute a vital component of the histone code. Aberrant O-GlcNAcylation of signaling proteins, metabolic enzymes, and transcriptional regulators can drive oncogenesis by dysregulating cellular proliferation, survival, and metabolic reprogramming. However, the effects of O-GlcNAcylation are not uniformly pro-oncogenic; context-dependent, tumor-suppressive, and protective functions have also been reported, underscoring the need for nuanced, cancer type-specific interpretation. OGT interacts with diverse epigenetic factors including HCF-1, TET, mSin3A, HDAC, and BAP1, linking the cellular metabolic state to the epigenetic profile of cancer cells.

In this review, we critically evaluate OGT's role in cancer epigenetics within a metabolism-epigenetics-signaling crosstalk framework, and discuss OGT inhibitor development and the challenges of therapeutic translation, including selectivity and bioavailability.