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Thiamet G for the study of O-GlcNAc homeostasis in pancreatic cancer

 

O-GlcNAcylation is a reversible post-translational protein modification involved in regulation of gene expression, cellular metabolism and signalling. The level of O-glycosylation is governed by O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). It has attracted attention as potential cancer drug target since major oncogenic factors p53, MYC, NFκB and β-catenin appear to be O-GlcNAcylated.

 

The study performed by Quin et al. looked at the transcriptional regulation of the O-GlcNAcylation homeostasis by inactivating OGA either genetically (OGA knockout) or pharmacologically with O-GlcNAcase inhibitor Thiamet G (TMG) from Carbosynth.

Thiamet G - Dynamic O-GlcANcylation

Transcriptional profiling of OGA inactivated cell lines showed a drop in OGT mRNA levels and increase in OGA mRNA levels, indicating that the OGA-OGT loop is controlled also at the transcriptional level. Moreover, the bioinformatic analysis of gene expression data from 32 types of cancer revealed positive correlation between OGT and OGA mRNA levels. This is reflected also in the OGT and OGA protein levels in pancreatic cancer model strengthening the fact that to a crucial role of protein O-GlcNAcylation in cancer pathogenesis.

Thiamet G - OGA assay

OGA enzymatic activity in cell lysates was assayed with fluorogenic substrate 4MU-GlcNAc (Ex368/Em450 nm). The OGA activity was normalized by subtracting the fluorescence resulting from lysosomal hexosaminidase contamination, which was assessed using 4MU-GalNAc.

 

For more details, read the original paper published in the Journal of Biological Chemistry: Qian et al., 2018.

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