ZDHHC9, also known as Zinc Finger DHHC-Type Containing 9 protein, functions as a palmitoyltransferase. Palmitoylation, a protein post-translational modification it mediates, is involved in various signaling pathways, playing a key role in biological processes and disease development [6].

In cancer, ZDHHC9 has been found to be oncogenic. In bladder cancer, its knockdown inhibits tumor proliferation, promotes apoptosis, and enhances drug efficacy. Mechanistically, it binds to and palmitoylates Bip protein at Cys420, inhibiting the unfolded protein response [1]. In colon cancer, inhibition of ZDHHC9 expression promotes in-vitro cancer cell proliferation but decreases in-vivo growth, and enhances CD8+ T-cell-mediated cytotoxicity [3]. In pancreatic cancer, knockdown of ZDHHC9 suppresses tumor progression by modifying the tumor microenvironment and sensitizes anti-PD-L1 immunotherapy [4]. In lung adenocarcinoma, ZDHHC9 deficiency inhibits cell proliferation, migration, and invasion, and promotes apoptosis. ZDHHC9 knockdown also reduces PD-L1 palmitoylation, promoting its degradation and enhancing anti-tumor immunity [8]. In glioblastoma, knockout of DHHC9 (ZDHHC9) abrogates GLUT1 palmitoylation, impairs glycolysis, cell proliferation, and tumorigenesis [7]. In cardiomyocytes, zDHHC9 palmitoylates Rab3gap1, regulating Rab3a activity and atrial natriuretic peptide secretion, which may be exploited for heart-failure treatment [2]. Regarding gasdermin D, ZDHHC9 is one of the major palmitoyltransferases mediating its palmitoylation, which is important for pyroptosis-related pore formation [5,9].

In conclusion, ZDHHC9, as a palmitoyltransferase, is crucial in multiple biological processes. Its role in various diseases, especially cancers and heart-related conditions, has been revealed through loss-of-function experiments. These findings suggest ZDHHC9 could be a potential therapeutic target for treating bladder, colon, pancreatic, lung, and glioblastoma cancers, as well as heart failure.

References:

1. Li, Weiquan, Liu, Jingchong, Yu, Tiexi, Yang, Hongmei, Zhang, Xiaoping. 2024. ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer progression. In Cancer letters, 598, 217118. doi:10.1016/j.canlet.2024.217118. https://pubmed.ncbi.nlm.nih.gov/39002690/

2. Essandoh, Kobina, Subramani, Arasakumar, Ferro, Olivia A, Koripella, Sribharat, Brody, Matthew J. 2023. zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1. In JACC. Basic to translational science, 8, 518-542. doi:10.1016/j.jacbts.2022.11.003. https://pubmed.ncbi.nlm.nih.gov/37325411/

3. Chong, Xiaodan, Zhu, Lingxi, Yu, Dong, Chen, Haitao, An, Huazhang. 2022. ZDHHC9 promotes colon tumor growth by inhibiting effector T cells. In Oncology letters, 25, 5. doi:10.3892/ol.2022.13591. https://pubmed.ncbi.nlm.nih.gov/36419754/

4. Lin, Zhiqing, Huang, Keke, Guo, Hui, Chen, Jiangfan, Guo, Wei. 2023. Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 161, 114567. doi:10.1016/j.biopha.2023.114567. https://pubmed.ncbi.nlm.nih.gov/36963362/

5. Du, Gang, Healy, Liam B, David, Liron, Lieberman, Judy, Wu, Hao. 2024. ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D. In Nature, 630, 437-446. doi:10.1038/s41586-024-07373-5. https://pubmed.ncbi.nlm.nih.gov/38599239/

6. Ramos, Anna Karolina Silva, Caldas-Rosa, Erica Carine Campos, Ferreira, Bárbara Merfort, Pic-Taylor, Aline, Mazzeu, Juliana F. 2022. ZDHHC9 X-linked intellectual disability: Clinical and molecular characterization. In American journal of medical genetics. Part A, 191, 599-604. doi:10.1002/ajmg.a.63052. https://pubmed.ncbi.nlm.nih.gov/36416207/

7. Zhang, Zhenxing, Li, Xin, Yang, Fan, Zeng, Yi-Xin, Li, Xinjian. 2021. DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis. In Nature communications, 12, 5872. doi:10.1038/s41467-021-26180-4. https://pubmed.ncbi.nlm.nih.gov/34620861/

8. Li, Zhe, Jiang, Da, Liu, Fengling, Li, Ying. 2023. Involvement of ZDHHC9 in lung adenocarcinoma: regulation of PD-L1 stability via palmitoylation. In In vitro cellular & developmental biology. Animal, 59, 193-203. doi:10.1007/s11626-023-00755-5. https://pubmed.ncbi.nlm.nih.gov/37002491/

9. Balasubramanian, Arumugam, Hsu, Alan Y, Ghimire, Laxman, Lieberman, Judy, Luo, Hongbo R. 2024. The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis. In Science immunology, 9, eadn1452. doi:10.1126/sciimmunol.adn1452. https://pubmed.ncbi.nlm.nih.gov/38530158/