Zdhhc20, a member of the ZDHHC palmitoyltransferase (ZDHHC-PAT) family, is involved in S-palmitoylation, a reversible fatty acyl modification. This process modifies proteins by adding a palmitoyl group to cysteine residues, which can affect protein activity, stability, localization, and interactions. Zdhhc20-mediated palmitoylation is associated with multiple biological pathways and is of great importance in various physiological and pathological processes [4,5]. Genetic models, such as knockout mouse models, have been valuable in studying its function.

In pancreatic cancer, Zdhhc20, upregulated by KRAS, promotes cancer progression. It inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, leading to abnormal accumulation of MYC and promoting cancer cell malignant phenotypes. Also, it promotes pancreatic cancer metastasis by affecting the interaction between tumor cells and the innate immune system [1,2]. In hepatocellular carcinoma (HCC), Zdhhc20 knockout significantly reduces hepatocarcinogenesis induced by chemical agents. Zdhhc20 palmitoylates fatty acid synthase (FASN) at cysteines 1471 and 1881, and its knockout or inhibition accelerates FASN degradation. Moreover, in HCC, Zdhhc20 knockdown inhibits cell proliferation and promotes apoptosis, while overexpression has the opposite effects by activating the PI3K-AKT signaling pathway [3,4].

In conclusion, Zdhhc20 plays essential roles in cancer-related biological processes, especially in pancreatic cancer and hepatocellular carcinoma, as revealed through gene knockout mouse models. These models have significantly contributed to understanding how Zdhhc20-mediated palmitoylation affects protein function and disease-associated pathways, providing potential therapeutic targets for these cancers.

References:

1. Zhang, Huan, Sun, Yan, Wang, Zhaokai, Jiang, Ke, Jin, Xin. 2024. ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression. In Nature communications, 15, 4642. doi:10.1038/s41467-024-49105-3. https://pubmed.ncbi.nlm.nih.gov/38821916/

2. Tomić, Goran, Sheridan, Clare, Refermat, Alice Y, Tate, Edward W, Downward, Julian. 2024. Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis. In Cell reports, 43, 114224. doi:10.1016/j.celrep.2024.114224. https://pubmed.ncbi.nlm.nih.gov/38733589/

3. Mo, Yaqi, Han, Yamei, Chen, Yang, Xiao, Mingming, Xu, Bo. 2024. ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis. In Molecular cancer, 23, 274. doi:10.1186/s12943-024-02195-5. https://pubmed.ncbi.nlm.nih.gov/39696259/

4. Huang, Xiaoju, Wang, Mengmeng, Zhang, Dan, Meng, Junpeng, Liu, Pian. 2024. ZDHHC20 Activates AKT Signaling Pathway to Promote Cell Proliferation in Hepatocellular Carcinoma. In Journal of hepatocellular carcinoma, 11, 1763-1775. doi:10.2147/JHC.S457682. https://pubmed.ncbi.nlm.nih.gov/39309302/

5. Azizi, Saara-Anne, Delalande, Clémence, Lan, Tong, Qiu, Tian, Dickinson, Bryan C. 2022. Charting the Chemical Space of Acrylamide-Based Inhibitors of zDHHC20. In ACS medicinal chemistry letters, 13, 1648-1654. doi:10.1021/acsmedchemlett.2c00336. https://pubmed.ncbi.nlm.nih.gov/36262404/