Abstract
Nuclear factor-kappaB (NF-κB) is a pleiotropic, evolutionarily conserved transcription factor family that plays a central role in regulating immune responses, inflammation, cell survival, and apoptosis. Great strides have been made in the past three decades to understand the role of NF-κB in physiological and pathological conditions. Carcinogenesis is associated with constitutive activation of NF-κB that promotes tumor cell proliferation, angiogenesis, and apoptosis evasion. NF-κB is ubiquitously expressed, however, its activity is under tight regulation by inhibitors of the pathway and through multiple posttranslational modifications. O-GlcNAcylation is a dynamic posttranslational modification that controls NF-κB-dependent transactivation. O-GlcNAcylation acts as a nutrient-dependent rheostat of cellular signaling. Increased uptake of glucose and glutamine by cancer cells enhances NF-κB O-GlcNAcylation. Growing evidence indicates that O-GlcNAcylation of NF-κB is a key molecular mechanism that regulates cancer cell proliferation, survival and metastasis and acts as link between inflammation and cancer. In this review, we are attempting to summarize the current understanding of the cohesive role of NF-κB O-GlcNAcylation in inflammation and cancer.
Highlights
The nuclear factor kappaB (NF-κB) family is a highly conserved group of master transcription factors critical in regulating cellular functions including cell survival, proliferation, differentiation, apoptosis, and immune response
O-GlcNAcylation regulates a plethora of cellular functions, including cell survival, apoptosis, cell cycle, cell proliferation, stress response, and immune response, by controlling transcription, translation, and protein stability
This review summarizes the current knowledge on NF-κB O-GlcNAcylation as a molecular mechanism that connects inflammation and cancer, and discusses its potential therapeutic implications and future perspectives
Summary
The nuclear factor kappaB (NF-κB) family is a highly conserved group of master transcription factors critical in regulating cellular functions including cell survival, proliferation, differentiation, apoptosis, and immune response. O-GlcNAcylation regulates a plethora of cellular functions, including cell survival, apoptosis, cell cycle, cell proliferation, stress response, and immune response, by controlling transcription, translation, and protein stability. Elevated global protein O-GlcNAcylation is a common finding in several solid cancers including breast (Caldwell et al, 2010; Krzeslak et al, 2012), prostate (Lynch et al, 2012), colorectal (Mi et al, 2011), and liver (Zhu et al, 2012). These cancers are associated with dysregulated NF-κB function, which contributes to tumorigenesis (Xia et al, 2014). Enhanced p65 nuclear translocation can be correlated with the decreased interaction between Thr-352 O-GlcNAcylated p65 and its physiological repressor, IκBα
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