UGDH, or UDP-glucose-6-dehydrogenase, is a cytosolic, hexameric enzyme. It converts UDP-glucose to UDP-glucuronic acid (UDP-GlcUA), a key reaction in hormone and xenobiotic metabolism, as well as in the production of extracellular matrix precursors. It is involved in multiple biological processes and is associated with pathways relevant to cancer and other diseases. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying UGDH's function [1].

In ovarian cancer, high UGDH expression in high-grade serous ovarian cancers shows subtype-specific prognostic significance. Knockdown of UGDH in the C1/Mesenchymal subtype reduces spheroid formation, viability, and the tumor-initiating cell population, while overexpression in the C4/Differentiated subtype has the opposite effect on the tumor-initiating cell population. In co-culture models, UGDH affects gene expression in mesothelial cells and fibroblast collagen production. Knockdown of UGDH in C1/Mesenchymal subtype mouse intrabursal xenografts improves survival and reduces tumor burden [2]. In lung cancer, phosphorylated UGDH enhances SNAI1 mRNA stability after EGFR activation, promoting epithelial-mesenchymal transition and tumor metastasis. Phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis [3]. In non-alcoholic steatohepatitis (NASH), UGDH absence from hepatocytes in male mice hastens liver damage, as UGDH suppresses RIPK1-dependent hepatocyte apoptosis by converting UDP-glucose to UDP-glucuronate, which binds to and inhibits RIPK1 activation [4].

In conclusion, UGDH is crucial for various metabolic and extracellular matrix-related processes. Model-based research, especially KO/CKO mouse models, has revealed its significant roles in cancer and NASH. Understanding UGDH's function in these disease areas can potentially lead to new therapeutic strategies for ovarian cancer, lung cancer, and NASH-associated liver damage.

References:

1. Price, Meghan J, Nguyen, Annee D, Byemerwa, Jovita K, Baëta, César D, Goodwin, C Rory. 2023. UDP-glucose dehydrogenase (UGDH) in clinical oncology and cancer biology. In Oncotarget, 14, 843-857. doi:10.18632/oncotarget.28514. https://pubmed.ncbi.nlm.nih.gov/37769033/

2. Harrington, Brittney S, Kamdar, Rahul, Ning, Franklin, Hooper, John D, Annunziata, Christina M. 2023. UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer. In Journal of experimental & clinical cancer research : CR, 42, 270. doi:10.1186/s13046-023-02820-z. https://pubmed.ncbi.nlm.nih.gov/37858159/

3. Wang, Xiongjun, Liu, Ruilong, Zhu, Wencheng, Li, Guohui, Yang, Weiwei. 2019. UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis. In Nature, 571, 127-131. doi:10.1038/s41586-019-1340-y. https://pubmed.ncbi.nlm.nih.gov/31243371/

4. Zhang, Tao, Zhang, Na, Xing, Jing, Xu, Daichao, Gu, Jinyang. 2023. UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis. In Nature communications, 14, 2715. doi:10.1038/s41467-023-38371-2. https://pubmed.ncbi.nlm.nih.gov/37169760/