PUBLICATION
A Role for Microsomal Glutathione Transferase 1 in Melanin Biosynthesis and Melanoma Progression
- Authors
- Zhang, J., Ye, Z.W., Bräutigam, L., Chakraborty, P., Luo, Z., Culpepper, J., Aslam, M., Zhang, L., Johansson, K., Haeggström, J.Z., Xu, J., Olsson, M., Townsend, D.M., Mehrotra, S., Morgenstern, R., Tew, K.D.
- ID
- ZDB-PUB-230616-37
- Date
- 2023
- Source
- The Journal of biological chemistry 299(8): 104920 (Journal)
- Registered Authors
- Aslam, Muhammad, Bräutigam, Lars, Culpepper, John, Tew, Kenneth, Townsend, Danyelle, Ye, Zhiwei, Zhang, Jie, Zhang, Leilei
- Keywords
- none
- MeSH Terms
-
- Animals
- Antioxidants
- Glutathione
- Glutathione Transferase*/metabolism
- Humans
- Melanins
- Melanoma*
- Mice
- Zebrafish/metabolism
- PubMed
- 37321450 Full text @ J. Biol. Chem.
Citation
Zhang, J., Ye, Z.W., Bräutigam, L., Chakraborty, P., Luo, Z., Culpepper, J., Aslam, M., Zhang, L., Johansson, K., Haeggström, J.Z., Xu, J., Olsson, M., Townsend, D.M., Mehrotra, S., Morgenstern, R., Tew, K.D. (2023) A Role for Microsomal Glutathione Transferase 1 in Melanin Biosynthesis and Melanoma Progression. The Journal of biological chemistry. 299(8):104920.
Abstract
Recent advancements in the treatment of melanoma are encouraging, but there remains a need to identify additional therapeutic targets. We identify a role for microsomal glutathione transferase 1 (MGST1) in biosynthetic pathways for melanin, and as a determinant of tumor progression. Knockdown (KD) of MGST1 depleted midline-localized, pigmented melanocytes in zebrafish embryos, while in both mouse and human melanoma cells, loss of MGST1 resulted in a catalytically dependent, quantitative and linear depigmentation, associated with diminished conversion of L-dopa to dopachrome (eumelanin precursor). Melanin, especially eumelanin, has antioxidant properties and MGST1 KD melanoma cells are under higher oxidative stress, with increased reactive oxygen species, decreased antioxidant capacities, reduced energy metabolism and ATP production, and lower proliferation rates in 3D culture. In mice, when compared to non-target control, Mgst1 KD B16 cells had less melanin, more active CD8+ T cell infiltration, slower growing tumors, and enhanced animal survival. Thus, MGST1 is an integral enzyme in melanin synthesis and its inhibition adversely influences tumor growth.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping