Oga, short for O-GlcNAcase, is the sole human enzyme responsible for catalyzing the hydrolysis (deglycosylation) of O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates [1]. O-GlcNAcylation is a reversible post-translational modification that regulates various cellular processes such as signal transduction, cell cycle, metabolism, and energy homeostasis [4]. Oga is thus crucial in maintaining the balance of O-GlcNAcylation levels in cells, which is important for normal cellular function. Dysregulation of O-GlcNAcylation, influenced by Oga, has been implicated in the pathogenesis of diseases like cancer, diabetes, and neurodegeneration [3,4].

In a study on cancer-derived Oga mutants, a point mutation in the non-catalytic stalk domain of Oga aberrantly modulated its interactome and substrate deglycosylation. Specifically, the mutant preferentially deglycosylated protein substrates with +2 proline relative to the O-GlcNAcylation site. One such substrate, PDLIM7, was found to suppress p53 gene expression and accelerate p53 protein degradation, while also augmenting cancer cell motility and aggressiveness. This reveals an important role of Oga's stalk domain in protein substrate recognition and functional modulation during malignant cell progression [1]. Another study showed that in lung cancer cells, the multifunctional protein RBM14 promotes ubiquitin-dependent proteasomal degradation of Oga, mediating cellular O-GlcNAcylation levels. Mutation of serine 521 on RBM14 abrogated its oncogenic properties, suggesting a potential therapeutic target for cancers with dysregulated O-GlcNAcylation [2].

In conclusion, Oga is essential for maintaining O-GlcNAcylation homeostasis in cells, and its dysregulation can lead to various disease states, especially cancer. Studies on Oga mutants and the regulation of Oga protein stability in cancer models have provided insights into its role in cancer development, highlighting its potential as a therapeutic target in cancer treatment.