Figure 1. Increased O-GlcNAc levels induces transcription of proliferative genes.

Graphical representation of transcriptional pathways that regulate and are regulated by O-GlcNAc to promote cell proliferation. Non-voltage dependent Ca2+ channel TRPM7 regulates O-GlcNAc levels in an unknown mechanism and increased O-GlcNAc serve to O-GlcNAcylate and stabilize Calveolin 1 and c-MYC. O-GlcNAc levels are also regulated by a mechanism in which RANBP2 SUMOylates CEBP-a, inducing its degradation and blocking OGA transcription which leads to increased O-GlcNAc levels. Increased O-GlcNAc increases NANOG, aldehyde dehydrogenase (ALDH), and Kruppel-like factor 8 (KLF8) levels, and O-GlcNAcylates SOX2 at Ser246 promoting its nuclear translocation. All of these transcription factors are considered to be Cancer Stem Cell (CSC) markers that promote tumor initiation/proliferation and epithelial to mesenchymal transition (EMT). Simultaneously, increased O-GlcNAc promotes O-GlcNAcylation of transcription factor SMAD4 which induces TGF-b production that also promotes EMT. In parallel, increased O-GlcNAc levels create an O-GlcNAc driven highly proliferative chromatin region which overlaps with markers of active promoters and super-enhancers, particularly c-MYC and host cell factor 1 (HCF-1) both of which are O-GlcNAcylated and regulate transcription of Cyclin B and polo-like kinase 1 (PLK1) which drive proliferation. Metastasis associated protein 1 (MTA1) is also O-GlcNAcylated which promotes its interaction with gene promoters involved in chemoresistance only under this modification. Finally, under increased OGT levels, YAP/TAZ is O-GlcNAcylated at Ser 109 and Thr 241 both of which inhibit phosphorylation of YAP/TAZ at Ser127 consequently blocking its cytoplasmic retention. O-GlcNAcylated YAP/TAZ translocates to the nucleus where it binds its transcriptional co-activator TEAD and promotes transcription of genes involved in cell survival and replication.