Scholarlink

<p>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 (MB<sub>SHH</sub>). Here, we demonstrate the role of S-palmitoylation and depalmitoylation of GLI1 in the regulation of incidence and progression of MB<sub>SHH</sub>. High expression of acyltransferase ZDHHC13 in MB<sub>SHH</sub> 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 MB<sub>SHH</sub>. Conversely, the deacylase ABHD17A depalmitoylates GLI1 at Cys1034, destabilizes GLI1, and in turn inactivates this signaling pathway. As a result, conditional knockout of <i>Zdhhc13</i> in cerebellar granule neuron precursors (GNPs) significantly alleviates the severity of MB<sub>SHH</sub> induced by constitutively active Smoothened (<i>Smo-M2</i>) overexpression and markedly extends overall survival, whereas knockout of <i>Abhd17a</i> increases the incidence of MB<sub>SHH</sub> induced by <i>Patched-1</i> 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 MB<sub>SHH</sub>.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Dynamic S-palmitoylation of glioma-associated oncogene 1 regulates the incidence and progression of Sonic Hedgehog medulloblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月29日

查看全文
  • Tingyu Shen,
  • Hangyang Bao,
  • Jirong Wang,
  • Xing Ji,
  • Weizhong Gu,
  • Chao Tang,
  • Qiangqiang He,
  • Jiahao Luo,
  • Dan Tan,
  • Jiali Yao,
  • Chengyun Xu,
  • Ying Gong,
  • Ximei Wu,
  • Shi-Hong Zhang,
  • Ling-Hui Zeng

摘要

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.