UGDH

What is UGDH protein?

UGDH gene (UDP-glucose 6-dehydrogenase) is a protein coding gene which situated on the short arm of chromosome 4 at locus 4p14. The protein encoded by this gene converts UDP-glucose to UDP-glucuronate and thereby participates in the biosynthesis of glycosaminoglycans such as hyaluronan, chondroitin sulfate, and heparan sulfate. These glycosylated compounds are common components of the extracellular matrix and likely play roles in signal transduction, cell migration, and cancer growth and metastasis. The expression of this gene is up-regulated by transforming growth factor beta and down-regulated by hypoxia. The UGDH protein is consisted of 494 amino acids and UGDH molecular weight is approximately 55.0 kDa.

What is the function of UGDH protein?

UGDH is involved in the synthesis of glycosaminoglycan such as hyaluronic acid, chondroitin sulfate, and heparin sulfate, which are major components of the extracellular matrix and have potential roles in cell signaling, cell migration, and cancer growth and metastasis. UGDH plays a role in carbohydrate metabolism, particularly in the pentose phosphate pathway, where it is responsible for catalyzing the production of UDP-gluconic acid, which is essential for the synthesis of hyaluronic acid and other glycosaminoglycan. The function of UGDH may influence the behavior of immune cells in the tumor microenvironment and regulate the immune response, which provides a new perspective for cancer treatment. UGDH is necessary for the proper development of the brain and neurons, and it plays a role in embryonic development through its role in the biosynthesis of glycosaminoglycans.

UGDH Related Signaling Pathway

UGDH interacts with typical growth factor signaling pathways such as MEK/ERK and PI3K/AKT signaling pathways, which may affect the proliferation, survival and metastasis of tumor cells. UGDH, as a key enzyme in the metabolic pathway, catalyzes the conversion of UDP-glucose to UDP-glucuronic acid and participates in the biosynthesis of glycosaminoglycans, which may affect cell signaling and metabolic characteristics of tumor cells. By promoting the synthesis of extracellular matrix components such as hyaluronic acid, UGDH is involved in regulating the tumor microenvironment and affecting the invasion and metastasis of tumor cells. In addition, UGDH also interacts with metabolic pathways and autophagy pathways.

UGDH Related Diseases

Abnormal functioning of UGDH or changes in its expression levels have been linked to a variety of diseases, especially cancer. For example, UGDH is upregulated in many types of cancer, including lung adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC), and its high expression is associated with tumor proliferation, invasion, metastasis and chemotherapy resistance. In addition, UGDH is also related to the regulation of tumor microenvironment, autophagy process, and the cross-regulation of signaling pathways such as EGFR, affecting the migration ability of tumor cells and lung cancer metastasis. In non-neoplastic diseases, the abnormal function of UGDH may also be associated with metabolic diseases and other pathological states.

Fig1. Hypothetical model representing the effect of UGDH knockdown in metastatic ovarian cancer cells. (Li-Hsun Lin, 2020)

Bioapplications of UGDH

The metabolic pathway of UGDH and its specific role in cancer have made it a hot spot in drug development. Research and development of drugs that can regulate the activity of UGDH may help treat diseases associated with UGDH, such as certain types of cancer. The expression level of UGDH may vary in some diseases, so it can be used as a biomarker for early diagnosis and monitoring of diseases, especially in the diagnosis of cancer. UGDH plays a key role in the synthesis of extracellular matrix, so it has potential for applications in tissue engineering and regenerative medicine that may help improve tissue repair and regeneration processes.

Case Study 1: Bao Guo, 2022

As the first-generation targeted therapy, sorafenib remains an effective single-drug treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, the existence of resistance restricts the long-term benefit of patients. In this study, researchers explore its critical role in regulating sorafenib sensitivity. The study revealed sorafenib exposure could activate glucuronic acid metabolism, accompanied with the elevated expression of UGDH. Interference with the route by silencing UGDH could boost HCC cells sensitivity to sorafenib. Further screening assay suggested that unfolded protein response (UPR) involves in UGDH silencing-mediated apoptosis. Xenograft model confirmed that combined UGDH intervention could significantly improve sorafenib efficacy.

Fig1. Western blot showing UGDH expression after cells were treated with sorafenib.

Fig2. UGDH depletion could inhibit UPR of HCC cells.

Case Study 2: Li-Hsun Lin, 2020

More than 70% of patients with ovarian cancer are diagnosed in advanced stages. Therefore, it is urgent to identify a promising prognostic marker and understand the mechanism of ovarian cancer metastasis development. Previous reports demonstrated that UGDH is involved in cell migration, but its specific role in cancer metastasis remains unclear. By performing immunohistochemical staining with tissue microarray, researchers found overexpression of UGDH in ovarian cancer tissue, but not in normal adjacent tissue. Silencing using RNA interference (RNAi) was utilized to knockdown UGDH, which resulted in a significant decrease in metastatic ability in transwell migration, transwell invasion and wound healing assays. The data showed that UGDH-depletion led to the down-regulation of epithelial-mesenchymal transition (EMT)-related markers as well as MMP2, and inactivation of the ERK/MAPK pathway.

Fig3. UGDH expression intensities were analysed by ImageJ.

Fig4. siUGDH-treated cells were monitored to assess the proliferation rates by MTT assay.

UGDH has several biochemical functions, for example, NAD binding,UDP-glucose 6-dehydrogenase activity,electron carrier activity. Some of the functions are cooperated with other proteins, some of the functions could acted by UGDH itself. We selected most functions UGDH had, and list some proteins which have the same functions with UGDH. You can find most of the proteins on our site.

UGDH has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with UGDH here. Most of them are supplied by our site. Hope this information will be useful for your research of UGDH.

SIRT3;UGT1A1;RAD51;ITGB1BP2;AK5;ere_dna;GRB2