Enhanced hexosamine metabolism drives metabolic and signaling networks involving hyaluronan production and O-GlcNAcylation to exacerbate breast cancer

Abstract

The hexosamine biosynthetic pathway (HBP) metabolically regulates dynamic cellular events by linking nutrient availability to numerous signaling networks. Significant alterations in the HBP are often associated with cancer pathogenesis. In this study, we investigated the molecular events underlying cancer pathogenesis associated with enhanced HBP flux. Multidimensional analysis of microarray datasets demonstrated up-regulation of genes encoding HBP enzymes in clinical breast cancers and revealed that co-expression of hyaluronan synthase 2 (HAS2) and glutamine:fructose-6-phosphate amidotransferase (GFAT), a rate-limiting enzyme of the HBP, was strongly correlated with a poor prognosis in advanced cancer patients. Consistently with the clinical data, comparative analyses of distinct breast cancer mouse models demonstrated enhancement of the HBP gene expression in primary carcinoma cells, with elevation of Has2 expression and hyaluronan production in aggressive breast cancer cells. The silencing of GFAT reduced CD44high/CD24low cancer stem cell (CSC)-like subpopulations, aldehyde dehydrogenase-positive cell populations, and mammosphere size, which were further diminished by gene targeting of Has2. Has2 gene disruption reduced the in vivo growth of aggressive cancer cells and attenuated pro-tumorigenic Akt/GSK3β/β-catenin signaling and cisplatin resistance. Overall protein O-GlcNAcylation was also elevated in association with HBP enhancement in aggressive cancer cells, and the modification exhibited overlapping but distinct roles from the hyaluronan signal in the regulation of CSC-like features. The current data therefore demonstrate that enhanced hexosamine metabolism drives pro-tumorigenic signaling pathways involving hyaluronan and O-GlcNAcylation in aggressive breast cancer.

Roles of Proteoglycans and Glycosaminoglycans in Cancer Development and Progression

“…Large quantities of HA in ECM stimulate interactions with CD44 to cause chemoresistance in patients with head and neck cancer patients [ 244 ]. HA activates growth signals, such as the PI3K/Akt pathway, thus leading to chemotherapy resistance in breast cancer [ 245 ]. By activation of TGFβ/Smad2 signals and ECM, HA-HMMR conferred resistance to chemotherapy in gastric cancer [ 246 ].…”

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

“…New inhibitors for GFAT are also in development (30)(31)(32). Another advantage of targeting GFAT/HBP is that inhibition of the pathway itself has anti-cancer properties, as we (13)and others have demonstrated (33)(34)(35)(36). HBP is frequently hyperactive in cancer cells.…”

Cell Energy Metabolism and Hyaluronan Synthesis

“…Multidimensional analysis of microarray datasets demonstrated that HBP enzymes are up-regulated in breast cancer and that the co-expression of HAS2 and the HBP rate limiting enzyme glutamine-fructose-6-phosphate transaminase (GFAT) is associated to a poor prognosis in advanced cancer patients. 73 Moreover, the enhancement of HBP flux is related to the activation of pro-tumorigenic pathways and elevated overall levels of O-GlcNAcylation. 73 The over-production of HA correlates to plasticity of breast cancer cells, where the acceleration of the metabolism of hexosamine, along with a metabolic shift toward glycolysis, reverts cancer cells phenotype to stem cell states.…”

“…73 Moreover, the enhancement of HBP flux is related to the activation of pro-tumorigenic pathways and elevated overall levels of O-GlcNAcylation. 73 The over-production of HA correlates to plasticity of breast cancer cells, where the acceleration of the metabolism of hexosamine, along with a metabolic shift toward glycolysis, reverts cancer cells phenotype to stem cell states. 74 The analysis of human breast cancer biopsies showed a dramatic increment of UDP-GlcNAc and UDP-GlcUA in the tumors, elevated GFAT levels and a strong accumulation of HA as compared to normal glandular tissue obtained from breast reductions.…”