T50 O-GlcNAc PKM2 promotes aerobic glycolysis and PDAC progression via ARNT-CDC27-AKT pathway

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and more evidence suggests that glucose metabolism plays a significant role in the development and progression with glycosylation at multiple sites potentially being a key characteristic. However, the underlying mechanisms remain insufficiently studied. Here, we first confirmed the presence of O-GlcNAc glycosylation modifications at Thr50 on PKM, which is highly expressed in PDAC and strongly correlated with poor prognosis. Further, we found that PKM expression was significantly positively correlated with CDC27 levels, and mutation of the Thr50 O-GlcNAc site in PKM abolished the upregulation of CDC27. We confirmed that O-GlcNAc-modified PKM enhances nuclear translocation of ARNT, which binds to the CDC27 promoter to upregulate its expression. Finally, we demonstrated that reduced expression of CDC27, as a key component of the APC/C complex, leads to downregulation of ubiquitination at the K11 site of PPP2CA, resulting in upregulation of PPP2CA expression, in turn, reduces AKT phosphorylation, ultimately driving PDAC regression by inhibiting aerobic glycolysis. Thus, we delineate a novel O-GlcNAcylation-dependent pathway where PKM drives PDAC progression through ARNT-mediated CDC27 transcriptional activation and AKT-mediated glycolysis.