Dynamic S-palmitoylation of glioma-associated oncogene 1 regulates the incidence and progression of Sonic Hedgehog medulloblastomaDownload PDF Download PDF ArticleOpen accessPublished: 29 June 2026Tingyu Shen ORCID: orcid.org/0009-0005-7640-97551,2,3 na1,Hangyang Bao1,2 na1,Jirong Wang ORCID: orcid.org/0000-0001-6172-852X4 na1,Xing Ji5,Weizhong Gu6,Chao Tang6,Qiangqiang He ORCID: orcid.org/0009-0004-5753-93621,2,Jiahao Luo1,2,Dan Tan1,2,Jiali Yao2,Chengyun Xu5,Ying Gong7,Ximei Wu ORCID: orcid.org/0000-0002-3316-893X1,2,Shi-Hong Zhang1,8 &…Ling-Hui Zeng3,5 Cell Death & Disease (2026) Cite this article We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.SubjectsCNS cancerPaediatric cancerTranscription factorsUbiquitylationAbstractAberrant activation of the Sonic Hedgehog (SHH)-glioma-associated oncogene 1 (GLI1) signaling pathway is a determinant driver of basal cell carcinoma (BCC) and SHH-subgroup medulloblastoma (MBSHH). Here, we demonstrate the role of S-palmitoylation and depalmitoylation of GLI1 in the regulation of incidence and progression of MBSHH. High expression of acyltransferase ZDHHC13 in MBSHH induces S-palmitoylation of human GLI1 at Cys1034, stabilizes GLI1 by preventing its ubiquitin-dependent proteasomal degradation, and in turn activates this signaling pathway to promote the progression of MBSHH. Conversely, the deacylase ABHD17A depalmitoylates GLI1 at Cys1034, destabilizes GLI1, and in turn inactivates this signaling pathway. As a result, conditional knockout of Zdhhc13 in cerebellar granule neuron precursors (GNPs) significantly alleviates the severity of MBSHH induced by constitutively active Smoothened (Smo-M2) overexpression and markedly extends overall survival, whereas knockout of Abhd17a increases the incidence of MBSHH induced by Patched-1 ablation, rather than its progression. Together, these findings uncover the dynamic regulation of GLI1 palmitoylation and depalmitoylation by the ZDHHC13 and ABHD17A and subsequent GLI1 stabilization and destabilization as a hitherto uncharacterized mechanism controlling SHH/GLI1 signaling and may provide additional targets for therapeutic intervention of MBSHH.AcknowledgementsWe thank Chong Liu from Zhejiang University School of Medicine for the GFAP-Cre mice and Zhang Lili from Hangzhou City University School of Medicine for the help of mouse MRI. The graphical abstract was drawn by Figdraw (www.figdraw.com).FundingThis work was supported by National Natural Science Foundation of China (No. 32170841, 31871395), National Key R&D Program of China (No. 2025YFA1109200), Key R&D Program of Zhejiang Province (No. 2022C03034), Zhejiang Provincial Natural Science Foundation of China (No. Z25H310004, LMS25H010002), and the Medical and Health Research Project of Zhejiang Province (No. 2023RC219).Author informationAuthor notesThese authors contributed equally: Tingyu Shen, Hangyang Bao, Jirong Wang.Authors and AffiliationsDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaTingyu Shen, Hangyang Bao, Qiangqiang He, Jiahao Luo, Dan Tan, Ximei Wu & Shi-Hong ZhangShulan International Medical College, Zhejiang Shuren University, Hangzhou, ChinaTingyu Shen, Hangyang Bao, Qiangqiang He, Jiahao Luo, Dan Tan, Jiali Yao & Ximei WuCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, ChinaTingyu Shen & Ling-Hui ZengZhejiang Provincial Key Lab of Geriatrics, Zhejiang Hospital, Hangzhou, ChinaJirong WangKey Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, ChinaXing Ji, Chengyun Xu & Ling-Hui ZengNational Clinical Research Center for Child Health, The Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, ChinaWeizhong Gu & Chao TangDepartment of Pharmacy, Hangzhou First People’s Hospital Affiliated of Westlake University School of Medicine, Hangzhou, ChinaYing GongDepartment of Anesthesiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaShi-Hong ZhangAuthorsTingyu ShenView author publicationsSearch author on:PubMed Google ScholarHangyang BaoView author publicationsSearch author on:PubMed Google ScholarJirong WangView author publicationsSearch author on:PubMed Google ScholarXing JiView author publicationsSearch author on:PubMed Google ScholarWeizhong GuView author publicationsSearch author on:PubMed Google ScholarChao TangView author publicationsSearch author on:PubMed Google ScholarQiangqiang HeView author publicationsSearch author on:PubMed Google ScholarJiahao LuoView author publicationsSearch author on:PubMed Google ScholarDan TanView author publicationsSearch author on:PubMed Google ScholarJiali YaoView author publicationsSearch author on:PubMed Google ScholarChengyun XuView author publicationsSearch author on:PubMed Google ScholarYing GongView author publicationsSearch author on:PubMed Google ScholarXimei WuView author publicationsSearch author on:PubMed Google ScholarShi-Hong ZhangView author publicationsSearch author on:PubMed Google ScholarLing-Hui ZengView author publicationsSearch author on:PubMed Google ScholarCorresponding authorsCorrespondence to Ximei Wu, Shi-Hong Zhang or Ling-Hui Zeng.Ethics declarationsCompeting interestsThe authors declare no competing interests.Ethics statementEthical approval for the use of human medulloblastoma tissue sections was granted by the Ethics Committee of the Children’s Hospital of Zhejiang University School of Medicine (Approval No. 2023-IRB-0233-P-01). Written informed consent, acknowledged as INFORMED, was obtained from all participants or their legal guardians. All procedures involving human tissues were performed in accordance with institutional ethical requirements, the Declaration of Helsinki (2024), and national guidelines. All animal experiments were approved by the Institutional Animal Care and Use Committee of Hangzhou City University School of Medicine (Protocol No. 23004) and conducted in accordance with the U.S. National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals, with all efforts made to minimize suffering and ensure animal welfare.Consent for publicationAll authors have approved this manuscript and consent to its publication.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Dr. Francesca BernassolaSupplementary informationSupplementary figures and table (download PDF )Original Western Blot (download PPTX )Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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