Functional consequences of FOXO3 O-GlcNAcylation in PDAC cells. Functional consequences of FOXO3 O-GlcNAcylation in PDAC cells. In normal cells with well-controlled glucose and hexosamine metabolism, FOXO3 is normally active and is not O-GlcNAcylated at its S284 residue. However, in PDAC cells, which usually exhibit abnormal glucose and hexosamine metabolism, excessive O-GlcNAc production by the activated HBP leads to the O-GlcNAcylation of FOXO3 at S284 (marked as “G” in purple hexagonal box). This site-specific O-GlcNAcylation, a molecular switch, might abrogate the tumor suppressor activity of FOXO3, which likely turns on MDM2 activity, which is known to degrade both p53 and p21. The activated MDM2-mediated degradation of p53 and p21 consequently runs into uncontrolled cell-cycle state. Green arrows indicate those pathways newly identified from this work, whereas blue arrows represent those already known. Heon Shin et al. Cancer Res 2018;78:1214-1224 ©2018 by American Association for Cancer Research