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. 2025 Sep 17;27(8):1972-1986.
doi: 10.1093/neuonc/noaf098.

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

Yang Wang  1 , Zhengxin Chen  1 , Rui Li  1 , Dong Wei  1 , Shuai Wang  2 , Hui Luo  1 , Yiming Tu  1 , Cen Liu  1 , Haibiao Xu  1 , Jiachen Xu  1 , Mingtian Ding  1 , Minghui Meng  1 , Tao Fu  1 , Yangyin Ding  1 , Jun Yin  1 , Wei Wu  1 , Jing Ji  3   1 , Huibo Wang  3   1
Affiliations

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

Yang Wang et al. Neuro Oncol. .

Abstract

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 xenograft models.

Conclusions: This study establishes the CK2α-zDHHC15-c-MET axis as a pivotal regulatory hub in GSC maintenance and identifies c-MET S-palmitoylation as a novel and promising therapeutic target for the treatment of glioblastoma.

Keywords: CK2α; S-palmitoylation; c-MET; glioblastoma stem cells; zDHHC15.

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Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Brennan CW, Verhaak RG, McKenna A, et al. ; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–477. - PMC - PubMed
    1. Frattini V, Trifonov V, Chan JM, et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet. 2013;45(10):1141–1149. - PMC - PubMed
    1. Stupp R, Mason WP, van den Bent MJ, et al. ; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. - PubMed
    1. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401. - PubMed
    1. Zhu Z, Khan MA, Weiler M, et al. Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival. Cell Stem Cell. 2014;15(2):185–198. - PubMed