Targeted O-GlcNAcylation Enables Functional Rewiring of c-Myc

It is notoriously difficult to directly target c-Myc, mainly due to its lack of well-defined druggable pockets. O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a post-translational modification (PTM) playing an important role in regulating c-Myc functions in cancer, while traditionally the studying methods perturbates global O-GlcNAcylation.

Here, we report a bifunctional O-GlcNAcylation TArgeting Chimera (OGTAC) molecule, which can induce the proximity of c-Myc and a fusion O-GlcNAc transferase (OGT) in living cells, and thereby enhancing the O-GlcNAcylation of c-Myc. The c-Myc-targeting OGTAC exhibits anti-proliferation effect on cancer cell line. Transcriptomic profiling indicates that OGTAC rewires c-Myc transcriptional activity and reprograms expression of the downstream oncogene MALAT1, in an O-GlcNAcylation-dependent manner.