Zdhhc6, also known as zinc finger-aspartate-histidine-cysteine 6, is a palmitoyltransferase. Protein palmitoylation is a post-translational modification that it is involved in, regulating the function and localization of various proteins. It is associated with multiple biological pathways, including lipid metabolism and inflammation-related signaling pathways, and is of great biological importance in processes such as tumorigenesis and the body's immune response [1,2,3,4,5,6,7]. Genetic models, like gene knockout mouse models, are valuable tools for studying Zdhhc6.

In colon cancer, Zdhhc6 promotes tumorigenesis. It directly interacts with and palmitoylates PPARγ at the Cys-313 site in its DNA binding domain, stabilizing PPARγ. This leads to the activation of the ACLY transcription-related metabolic pathway, stimulating fatty acid biosynthesis. Inhibition of Zdhhc6 expression in in vivo trials significantly reduces cancer-causing effects, and high Zdhhc6 expression is positively correlated with PPARγ expression, CRC severity, and poor prognosis [1]. In sepsis, Zdhhc6 palmitoylates MYD88 at cysteine 113. Zdhhc6 knockdown decreases MYD88 palmitoylation and TLR/MYD88 activation upon lipopolysaccharide stimulus, suggesting it as a therapeutic target for sepsis [2]. In hepatocellular carcinoma, Zdhhc6 dynamically regulates AEG-1 palmitoylation at Cys-75. Deletion of Zdhhc6 in a DEN-induced HCC mouse model enhances tumor-progression phenotype [3].

In conclusion, Zdhhc6 plays crucial roles in tumorigenesis, such as in colon and liver cancers, and in inflammation-related diseases like sepsis through its palmitoyltransferase function. Gene knockout mouse models have been instrumental in revealing these roles, providing insights into the underlying mechanisms and potential therapeutic targets for these disease areas.

References:

1. Shan, Junqi, Li, Xinyu, Sun, Runqi, Dai, Xianling, Sun, Yanlai. 2024. Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming. In Journal of experimental & clinical cancer research : CR, 43, 227. doi:10.1186/s13046-024-03154-0. https://pubmed.ncbi.nlm.nih.gov/39148124/

2. Kim, Young-Chan, Lee, Sang Eun, Kim, Somi K, Jang, Kyoung-Soon, Kim, Hyo-Soo. 2019. Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation. In Nature chemical biology, 15, 907-916. doi:10.1038/s41589-019-0344-0. https://pubmed.ncbi.nlm.nih.gov/31427815/

3. Zhou, Binhui, Wang, Ying, Zhang, Lichen, Zheng, Junfeng, Kong, Eryan. 2022. The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma. In Theranostics, 12, 6898-6914. doi:10.7150/thno.78377. https://pubmed.ncbi.nlm.nih.gov/36276642/

4. Qiu, Nan, Abegg, Daniel, Guidi, Mara, Seeberger, Peter H, Adibekian, Alexander. 2021. Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6. In Cell chemical biology, 29, 530-537.e7. doi:10.1016/j.chembiol.2021.07.012. https://pubmed.ncbi.nlm.nih.gov/34358442/

5. Salaun, Christine, Tomkinson, Nicholas C O, Chamberlain, Luke H. 2023. The endoplasmic reticulum-localized enzyme zDHHC6 mediates S-acylation of short transmembrane constructs from multiple type I and II membrane proteins. In The Journal of biological chemistry, 299, 105201. doi:10.1016/j.jbc.2023.105201. https://pubmed.ncbi.nlm.nih.gov/37660915/

6. Guo, He-Zhou, Feng, Rui-Xue, Zhang, Yan-Jie, Zhu, Jiang, Shi, Jun. 2024. A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML. In Cell reports. Medicine, 5, 101592. doi:10.1016/j.xcrm.2024.101592. https://pubmed.ncbi.nlm.nih.gov/38843841/

7. Komaniecki, Garrison, Camarena, Maria Del Carmen, Gelsleichter, Eric, Sarkar, Devanand, Lin, Hening. 2022. Astrocyte Elevated Gene-1 Cys75 S-Palmitoylation by ZDHHC6 Regulates Its Biological Activity. In Biochemistry, 62, 543-553. doi:10.1021/acs.biochem.2c00583. https://pubmed.ncbi.nlm.nih.gov/36548985/