Zdhhc8, zinc finger DHHC-domain containing protein 8, is a protein palmitoyl transferase (PAT). Palmitoylation, the modification of proteins with palmitate, is crucial for protein targeting and trafficking. Zdhhc8 is involved in various biological processes by catalyzing the palmitoylation of specific proteins, and is highly expressed in multiple tissues including the brain and tumors. Genetic models, such as Drosophila ortholog dZDHHC8 and gene knockdown in mammalian cells, are valuable for studying its functions [3,5].

In glioblastoma, AMPKα1-mediated Zdhhc8 phosphorylation promotes SLC7A11 palmitoylation, enhancing ferroptosis resistance. Knocking down Zdhhc8 impairs glioblastoma cell survival through promoting intracellular ferroptosis [1]. In epilepsy models, knocking down Zdhhc8 in mouse brains and in vitro seizure models delayed seizure precipitation and decreased chronic spontaneous recurrent seizures, while overexpression had the opposite effect. Zdhhc8 affects AMPA receptor-related excitatory glutamatergic synaptic neurotransmission [2]. In mesothelioma mouse models, Zdhhc8 knockdown enhanced radiosensitivity and suppressed tumor growth when combined with X-irradiation, likely through inducing chromosomal instability and apoptosis via an impaired G(2)/M checkpoint [4].

In summary, Zdhhc8 plays essential roles in processes like ferroptosis regulation, seizure susceptibility, and radiosensitivity in cancer through its function as a palmitoyl transferase. Studies using gene knockdown and other genetic models in relevant disease models have provided insights into its functions, suggesting Zdhhc8 could be a potential target for treating glioblastoma, epilepsy, and mesothelioma.

References:

1. Wang, Zhangjie, Wang, Yang, Shen, Na, Wei, Yunfei, Tang, Jingyuan. 2024. AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma. In Cancer letters, 584, 216619. doi:10.1016/j.canlet.2024.216619. https://pubmed.ncbi.nlm.nih.gov/38211651/

2. Yang, Qin, Zheng, Fangshuo, Hu, Yida, Wang, Qing, Wang, Xuefeng. 2018. ZDHHC8 critically regulates seizure susceptibility in epilepsy. In Cell death & disease, 9, 795. doi:10.1038/s41419-018-0842-0. https://pubmed.ncbi.nlm.nih.gov/30038264/

3. Strassburger, Katrin, Kang, Evangeline, Teleman, Aurelio A. 2019. Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability. In PloS one, 14, e0198149. doi:10.1371/journal.pone.0198149. https://pubmed.ncbi.nlm.nih.gov/30735487/

4. Sudo, Hitomi, Tsuji, Atsushi B, Sugyo, Aya, Sagara, Masashi, Saga, Tsuneo. 2011. ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model. In Cancer science, 103, 203-9. doi:10.1111/j.1349-7006.2011.02126.x. https://pubmed.ncbi.nlm.nih.gov/22017350/

5. Collura, Kaitlin M, Niu, Jingwen, Sanders, Shaun S, Holland, Sabrina M, Thomas, Gareth M. 2020. The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway. In The Journal of biological chemistry, 295, 15427-15437. doi:10.1074/jbc.RA120.013815. https://pubmed.ncbi.nlm.nih.gov/32958558/