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

Chatchadawalai Chokchaitaweesuk,Tomomi Izumikawa,Naoki Itano,Takashi Kobayashi

doi:10.1038/s41419-019-2034-y

Chatchadawalai Chokchaitaweesuk, Tomomi Izumikawa + Show 2 more

Open Access

https://doi.org/10.1038/s41419-019-2034-y

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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.

Highlights

Cancer cells reprogram metabolic pathways to optimally meet their energy and nutrient requirements
Oncomine microarray gene expression datasets were initially analyzed across different types of clinical breast cancers for the expression of genes encoding hexosamine biosynthetic pathway (HBP) enzymes, including glutamine:fructose-6-phosphate amidotransferase (GFAT), glucosamine-phosphate Nacetyltransferase 1 (GNPNAT1), phosphoglucomutase 3 (PGM3), and UDP-GlcNAc pyrophosphorylase 1 (UAP1), to investigate the molecular mechanisms underlying cancer pathogenesis associated with enhanced HBP flux[23,24]
Eight of 11 datasets showed that the expression of GFAT (GFAT1/2) was elevated over 1.5-fold in various types of breast cancers compared with normal samples

Summary

Introduction

Cancer cells reprogram metabolic pathways to optimally meet their energy and nutrient requirements. The most prominent metabolic alterations in cancer are an increase in glucose uptake and elevation of aerobic glycolysis, The nutrient-sensing hexosamine biosynthetic pathway (HBP) is a glucose metabolic pathway branching off from main glycolysis[8]. Official journal of the Cell Death Differentiation Association. Chokchaitaweesuk et al Cell Death and Disease (2019)10:803 diphosphate-N-acetylglucosamine (UDP-GlcNAc), which serves as a key metabolite essential for multiple protein glycosylations, glycosaminoglycan biosynthesis, and cellular signaling through protein O-GlcNAcylation. OGlcNAcylation is a post-translational modification that transfers a single O-GlcNAc moiety from UDP-GlcNAc to serine/threonine residues of proteins[9]. The modification occurs in a wide spectrum of intracellular proteins and regulates various distinct cellular processes, including transcription, translation, signal transduction, epigenetic regulation, and proteasomal degradation[9]. Given the diverse roles of O-GlcNAcylation, a potential link between hyper-O-GlcNAcylation and cancer progression has been proposed[10]

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