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Hyper‐O‐GlcNAcation links cancer metabolism to oncogenic signaling.
Author(s) -
Vosseller Keith,
Ma Zhiyuan
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.452.3
Subject(s) - warburg effect , cell growth , cancer cell , pancreatic cancer , apoptosis , cancer research , chemistry , cancer , gene silencing , cell , microbiology and biotechnology , reprogramming , signal transduction , biology , biochemistry , gene , genetics
Cancer cell metabolic reprogramming of energy production to the relatively inefficient glycolytic pathway (Warburg effect) necessitates increased glucose uptake. Glucose flux through the hexosamine biosynthetic pathway (HBP) leads to production of UDP‐ N ‐acetylglucosamine (UDP‐GlcNAc), used in enzymatic post‐translational modification of cytosolic/nuclear proteins by O‐linked β‐ N ‐acetylglucosamine (O‐GlcNAc). We observe increased HBP flux, elevated levels of the enzyme that adds O‐GlcNAc (OGT), and hyper‐O‐GlcNAcation in human cancers. Genetic and pharmacological reduction of cancer hyper‐O‐GlcNAcation inhibits transformed phenotypes. Silencing OGT to reduce O‐GlcNAc had no effect on non‐transformed pancreatic epithelial cell growth, but inhibited pancreatic ductal adenocarcinoma (PDAC) cell proliferation, anchorage‐independent growth, orthotopic tumor growth, and triggered apoptosis. Constitutive NF‐κB activity is anti‐apoptotic in many cancers. Reducing hyper‐O‐GlcNAcation decreased PDAC NF‐κB activation, while pharmacologically mimicking PDAC hyper‐O‐GlcNAcation activated NF‐κB. Specific mutation of two NF‐κB p65 subunit O‐GlcNAc sites (T322 and T352) to alanines reduced p65 O‐GlcNAcation and attenuated PDAC cell anchorage‐independent growth. Our data indicates that PDAC hyper‐O‐GlcNAcation is anti‐apoptotic and contributes to NF‐κB oncogenic activation.