S-palmitoylation of c-MET by CK2α-mediated zDHHC15 phosphorylation drives glioblastoma stem cell tumorigenicity

作者：Y.-P. Wang, Zhengxin Chen, Rui Li, Wei Dong, Shuai Wang, Hui Luo, Yiming Tu, Cen Liu, Hao Xu, Jiachen Xu, Mingtian Ding, Minghui Meng, Tao Fu, Yangyin Ding, Jun Yin, Wei Wu, Jing Ji, Huibo Wang · 发表于：Neuro-Oncology · 年份：2025 · DOI：10.1093/neuonc/noaf098 · 被引用次数：6 · 研究领域：Liver physiology and pathology、Cancer Cells and Metastasis、Cancer, Hypoxia, and Metabolism

BACKGROUND: The c-MET signaling pathway is crucial for the self-renewal and tumorigenic capacity of cancer stem cells, including glioblastoma stem cells (GSCs). Despite its recognized importance, the precise mechanisms of c-MET activation in these cells remain elusive. This study aimed to elucidate the key regulatory elements and mechanisms governing c-MET function in GSCs. METHODS: The mediation of S-palmitoylation and dimerization of c-MET by zDHHC15 was validated using metabolic labeling, acyl-PEG exchange (APE), BS3 crosslinking, and co-immunoprecipitation. The role of the CK2α-zDHHC15-c-MET axis in tumorigenesis, along with the antitumor efficacy of TVB-3166, was confirmed through cell proliferation, limiting dilution, and intracranial tumor growth assays. RESULTS: We revealed that zDHHC15, a member of the DHHC family of palmitoyl acyltransferases, mediates the palmitoylation of c-MET at Cys801, which is critical for c-MET O-glycosylation, dimerization, and activation. We further identified a novel regulatory loop in which CK2α phosphorylates zDHHC15 at Tyr92, increasing its stability and c-MET binding, thereby enhancing c-MET palmitoylation. zDHHC15 was found to be specifically enriched in GSCs, and its targeted knockdown markedly impaired their self-renewal and tumorigenic capabilities both in vitro and in vivo. Therapeutically, we introduced TVB-3166, an inhibitor of c-MET S-palmitoylation, which demonstrated robust inhibitory effects on GSC growth in orthotopic xenog...