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

BACKGROUND: 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. MAIN TEXT: 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. CONCLUSIONS: 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.