ZDHHC20, a member of the ZDHHC palmitoyltransferase (ZDHHC-PAT) family, is involved in protein S-palmitoylation, a reversible fatty acyl modification. This process undertakes important functions in multiple physiological processes, participating in regulating protein activity, stability, localization, and interactions. Genetic models, such as knockout mice, have been crucial in studying its functions [2,4].

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 promotion of cancer cell malignant phenotypes [1]. In hepatocellular carcinoma (HCC), knocking out ZDHHC20 significantly reduces hepatocarcinogenesis in mouse models. ZDHHC20 palmitoylates fatty acid synthase (FASN) at cysteines 1471 and 1881, and its knockout or pharmacological inhibition accelerates FASN degradation [2]. Also in HCC, ZDHHC20 knockdown inhibits cell proliferation and promotes apoptosis, while overexpression has the opposite effects, through activating the PI3K-AKT signaling pathway [4]. In pancreatic cancer metastasis, in vivo shRNA screen shows ZDHHC20 is critical for metastatic outgrowth, affecting the interaction of tumor cells and the innate immune system [3].

In conclusion, ZDHHC20 plays a significant role in promoting the development of pancreatic cancer and hepatocellular carcinoma through palmitoylation-related mechanisms. Gene knockout mouse models have been instrumental in revealing these functions, highlighting its potential as a therapeutic target in these diseases [1,2,3,4].