Transcriptional regulation of O‐GlcNAc homeostasis (607.8)

Abstract

A vast number of nuclear and cytoplasmic proteins are modified by O‐linked β‐N‐acetylglucosamine (O‐GlcNAc), a dynamic post‐translational modification that has emerged as a key regulator of diverse cellular processes. The addition and removal of O‐GlcNAc are catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), respectively. Accumulating evidence indicates that both excess and deficiency of O‐GlcNAc in the cell can have deleterious effects, suggesting that maintenance of O‐GlcNAc homeostasis is critical for cellular function. However, the mechanism by which O‐GlcNAc homeostasis is maintained in the normal state and disrupted in the disease state has not yet been investigated. Here, we demonstrate that Ogt expression is upregulated by OGA, creating a feedback mechanism that serves to maintain a balance between OGT and OGA expression levels in the cell. We found that OGA promotes Ogt transcription through cooperation with the histone acetyltransferase p300 and the transcription factor CCAAT‐enhancer‐binding protein β (C/EBP‐β). In this protein complex, OGA and p300 act as transcriptional coactivators of C/EBP‐β through their glycosidase and acetyltransferase activities, respectively. Since O‐GlcNAc homeostasis is often disrupted in cancer cells, we also sought to determine whether classical oncoproteins are involved in regulating Ogt expression. We found that extracellular signal‐regulated kinase (ERK) increases OGA glycosidase activity and promotes Ogt transcription, suggesting that chronic growth factor stimulation may be responsible for disrupted O‐GlcNAc homeostasis in cancer. Our study elucidates a transcriptional mechanism that controls cellular O‐GlcNAc homeostasis, which should lay a foundation for exploring O‐GlcNAc signaling as a therapeutic target for human disease.Grant Funding Source: Supported by NIH R01‐DK089098