Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling

Abstract

Cancer stem cells (CSCs) represent a small subpopulation of self-renewing oncogenic cells. As in many other stem cells, metabolic reprogramming has been implicated to be a key characteristic of CSCs. However, little is known about how the metabolic features of cancer cells are controlled to orchestrate their CSC-like properties. We recently demonstrated that hyaluronan (HA) overproduction allowed plastic cancer cells to revert to stem cell states. Here, we adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells. These integrated approaches disclosed an acceleration of metabolic flux in the hexosamine biosynthetic pathway (HBP). A metabolic shift toward glycolysis was also evident by quantitative targeted metabolomics, which was validated by the expression profiles of key glycolytic enzymes. Forced expression of glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), an HBP rate-limiting enzyme, resembled the results of HA overproduction with regard to HIF-1α accumulation and glycolytic program, whereas GFAT1 inhibition significantly decreased HIF-1α protein level in HA-overproducing cancer cells. Moreover, inhibition of the HBP-HIF-1 axis abrogated HA-driven glycolytic enhancement and reduced the CSC-like subpopulation. Taken together, our results provide compelling evidence that HA production regulates the metabolic and CSC-like properties of breast cancer cells via HBP-coupled HIF-1 signaling.

Dissecting the role of hyaluronan synthases in the tumor microenvironment

“…HAS2 expression is unusually high in basal-like and triple-negative tumors where HAS2 is a critical factor that induces epithelial-mesenchymal transition (EMT). HA and HAS2 have also been described to have crucial functions in determining cancer-initiating cells, or as cancer stem cells, that are believed to drive cancer growth and progression through aberrant self-renewal and generation of heterogeneous cancer cell lineages [21,88]. Collectively, we can propose a scenario where the presence of HA in the tumor microenvironment can affect not only cancer cell behavior but can also dramatically change other critical steps of tumorigenesis like immune cell infiltration and angiogenesis.…”

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

“…GFAT1 is ubiquitously expressed and GFAT2 is expressed in some tissues like heart, skeletal muscle, lung, and placenta, besides its elevated expression in the central nervous system (DeHaven et al, 2001). Although the relevance of HBP in cancer metabolism has been described in some types of carcinomas such as prostrate (Itkonen et al, 2016), lung (Alisson-Silva et al, 2013), breast (Chanmee et al, 2016), pancreas (Itkonen et al, 2016), and colon (Steenackers et al, 2016), the regulation of this pathway remains largely unknown in tumor cells. Although the relevance of HBP in cancer metabolism has been described in some types of carcinomas such as prostrate (Itkonen et al, 2016), lung (Alisson-Silva et al, 2013), breast (Chanmee et al, 2016), pancreas (Itkonen et al, 2016), and colon (Steenackers et al, 2016), the regulation of this pathway remains largely unknown in tumor cells.…”

“…Tumor cells up-regulate GFAT2 expression (Simpson et al, 2012). Although the relevance of HBP in cancer metabolism has been described in some types of carcinomas such as prostrate (Itkonen et al, 2016), lung (Alisson-Silva et al, 2013), breast (Chanmee et al, 2016), pancreas (Itkonen et al, 2016), and colon (Steenackers et al, 2016), the regulation of this pathway remains largely unknown in tumor cells. Recently, our group showed that GFAT activity plays an important role in the tumorigenesis of the colon cancer (Vasconcelos-Dos-Santos et al, 2017).…”

GFAT1/HBP/O-GlcNAcylation Axis Regulatesβ-Catenin Activity to Promote Pancreatic Cancer Aggressiveness

“…Indeed, reduced HBP flux leads to disordered glycosylation of proteins and subsequently induction of cell death [25]. Meanwhile, the decrease of protein glycosylation is lethal for many cancer cells which need protein glycosylation for oncogenic cellular functions [27].…”