ZDHHC20, a member of the ZDHHC palmitoyltransferase (ZDHHC-PAT) family, is involved in the reversible lipid modification known as palmitoylation [4]. Palmitoylation can affect the activity, stability, localization, and interactions of target proteins [5]. This process is crucial in multiple physiological processes, and ZDHHC20-mediated palmitoylation is associated with various biological pathways and disease-related processes. Gene knockout (KO) and conditional knockout (CKO) mouse models are valuable for studying ZDHHC20's function.

In pancreatic cancer, ZDHHC20, upregulated by KRAS, promotes cancer progression through S-palmitoylation of YTHDF3, which stabilizes MYC mRNA [1]. In hepatocellular carcinoma (HCC), knocking out ZDHHC20 in DEN-induced and DEN combined CCl4 HCC models significantly reduces hepatocarcinogenesis. ZDHHC20 mediates S-palmitoylation of fatty acid synthase (FASN), and its knockout or pharmacological inhibition accelerates FASN degradation [2]. In HCC, ZDHHC20 knockdown inhibits cell proliferation and promotes apoptosis, while overexpression has the opposite effects, acting through the PI3K-AKT signaling pathway [4]. In addition, in the context of pancreatic cancer metastasis, ZDHHC20 was identified in an in vivo shRNA screen as critical for metastatic outgrowth, and its effect is related to the interaction between tumor cells and the innate immune system [3].

In conclusion, ZDHHC20 is a key palmitoyltransferase with essential functions in regulating protein palmitoylation. Through KO/CKO mouse models, its role in promoting the progression of pancreatic cancer and hepatocellular carcinoma has been clearly demonstrated. These findings highlight the importance of ZDHHC20 in disease-related biological processes and suggest its potential as a therapeutic target.

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. 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/

3. 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/

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/