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. Author manuscript; available in PMC: 2020 Jan 16.
Published in final edited form as: Oncogene. 2019 Jul 15:10.1038/s41388-019-0885-4. doi: 10.1038/s41388-019-0885-4

Figure 1: Identification of UGDH as a clinically relevant metabolic enzyme associated with mesenchymal-like gene expression and cancer progression.

Figure 1:

A) Integrated gene expression analysis of breast cancer patient data, intrinsic cell lines, and in vitro models of EMT revealed 12 metabolic enzymes and transporters which are significantly associated with a mesenchymal-like gene signature. B) List of 12 metabolic genes upregulated in EMT models. C) Network visualization of metabolic pathways enriched among metabolic genes upregulated in EMT-TF models relative to control. Node size is proportional to pathway enrichment score, and node color is proportional to FDR-adjusted p-value. Edge size and color is proportional to the number of shared genes between two nodes. D) Elevated expression of Uridine Diphosphate Glucose Dehydrogenase (UGDH) expression is associated with decreased recurrence-free survival (RFS) among a cohort of ER-negative patients. E) Representative images of UGDH staining within the TMA. A score of “0” indicates the absence of UGDH staining whereas a score of “3” indicates intense UGDH staining. F) TMA scores grouped by breast cancer type shows UGDH is significantly elevated in invasive and metastatic forms of breast cancer compared to non-malignant samples. See Methods section for detailed group definitions. G) A simplified model of the metabolic context of UGDH and its direct product, uridine diphosphate glucuronic acid (UDP-GlcUA). Briefly, carbon from glucose is converted into uridine diphosphate glucose (UDP-glucose) via a series of metabolic reactions. The enzyme UGDH converts UDP-glucose to UDP-GlcUA. UDP-GlcUA is used as the substrate for glucuronidation reactions by UDP-glucuronosyltransferases (UGTs), which is important in clearance of xenobiotic metabolites. Additionally, UDP-GlcUA is used as a precursor for glycosylaminoglycans including Dermatan sulfate, Chondroitin sulfate, and hyaluronic acid. Hyaluronic acid is synthesized from hyaluronic acid synthases, including HAS2, which was identified along with UGDH as one of the 12 enzymes associated with mesenchymal-like gene expression. Together, this suggests that mesenchymal-like cells will increase UDP-glucuronic acid production and hyaluronic acid synthesis.