Dynamic S-palmitoylation of glioma-associated oncogene 1 regulates the incidence and progression of Sonic Hedgehog medulloblastoma
7 affiliations
- 1Department of Pharmacology, Zhejiang University School of Medicine
- 2Zhejiang Provincial Key Lab of Geriatrics, Zhejiang Hospital
- 3Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine
- 4National Clinical Research Center for Child Health, The Children’s Hospital of Zhejiang University School of Medicine
- 5Shulan International Medical College, Zhejiang Shuren University
- 6Department of Pharmacy, Hangzhou First People’s Hospital Affiliated of Westlake University School of Medicine
- 7College of Pharmaceutical Sciences, Zhejiang University
Abstract
Aberrant 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.
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BibTeX
@article{shen2026dynamic,
title = {{Dynamic S-palmitoylation of glioma-associated oncogene 1 regulates the incidence and progression of Sonic Hedgehog medulloblastoma}},
author = {Tingyu Shen and Hangyang Bao and Jirong Wang and Xing Ji and Weizhong Gu and Chao Tang and Qiangqiang He and Jiahao Luo and Dan Tan and Jiali Yao and Chengyun Xu and Ying Gong and Ximei Wu and Shi-Hong Zhang and Ling-Hui Zeng},
journal = {Cell Death and Disease},
year = {2026},
month = jun,
doi = {10.1038/s41419-026-09051-y},
url = {https://doi.org/10.1038/s41419-026-09051-y},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic S-palmitoylation of glioma-associated oncogene 1 regulates the incidence and progression of Sonic Hedgehog medulloblastoma
AU - Tingyu Shen
AU - Hangyang Bao
AU - Jirong Wang
AU - Xing Ji
AU - Weizhong Gu
AU - Chao Tang
AU - Qiangqiang He
AU - Jiahao Luo
AU - Dan Tan
AU - Jiali Yao
AU - Chengyun Xu
AU - Ying Gong
AU - Ximei Wu
AU - Shi-Hong Zhang
AU - Ling-Hui Zeng
PY - 2026
DA - 2026/06/01
JO - Cell Death and Disease
DO - 10.1038/s41419-026-09051-y
UR - https://doi.org/10.1038/s41419-026-09051-y
AB - Aberrant 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.
SN - 2041-4889
ER -