GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2-STAT3 axis.
GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2-STAT3 axis.
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ZDHHC4 介导的 GSK3β 棕榈酰化通过 EZH2-STAT3 轴促进替莫唑胺耐药胶质母细胞瘤中胶质母细胞瘤干细胞的致瘤性
DOI：
10.1038/s41389-022-00402-w
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发表时间：
2022-05-23
期刊：
影响因子：
6.2
通讯作者：
Chen, Xueran
中科院分区：
文献类型：
--
作者：
Zhao, Chenggang;Yu, Huihan;Fan, Xiaoqing;Niu, Wanxiang;Fan, Junqi;Sun, Suling;Gong, Meiting;Zhao, Bing;Fang, Zhiyou;Chen, Xueran
胶质母细胞瘤干细胞（GSCs）是胶质母细胞瘤（GBM）中一种高度致瘤性的细胞亚群。糖原合成酶激酶3β (GSK3β)被认为是促进GBM恶性表型的关键枢纽。然而，GSK3β和GSCs在GBM中的功能关系尚不清楚。在这里，我们发现GSK3β被认为是zdhhc4介导的Cys14残基棕榈酰化的底物，它增强了GBM对替莫唑胺（TMZ）的抗性和GSC的自我更新。临床发现，ZDHHC4在GBM中表达水平上调，与肿瘤分级及不良预后显著相关。上述表型是基于GSK3β棕榈酰化降低p-Ser9和增加p-Tyr216，进一步激活zeste同源物2 (EZH2) -STAT3途径的增强子。值得注意的是，STAT3沉默也抑制了ZDHHC4的表达。本研究发现，ZDHHC4介导的GSK3β棕榈酰化通过激活EZH2-STAT3信号轴，改善了TMZ耐药GBM的茎性，为进一步了解TMZ耐药及治疗后复发的机制提供了新的理论依据。
Glioblastoma stem cells (GSCs) are a highly tumorigenic cell subgroup of glioblastoma (GBM). Glycogen synthase kinase 3β (GSK3β) is considered a key hub for promoting malignant phenotypes in GBM. However, the functional relationships between GSK3β and GSCs in GBM are unclear. Here, we found that GSK3β was noted as a substrate for ZDHHC4-mediated palmitoylation at the Cys14 residue, which enhanced GBM temozolomide (TMZ) resistance and GSC self-renewal. Clinically, the expression level of ZDHHC4 was upregulated in GBM, which significantly correlated with tumor grade and poor prognosis. The above phenotypes were based on decreasing p-Ser9 and increasing p-Tyr216 by GSK3β palmitoylation, which further activated the enhancer of the zeste homolog 2 (EZH2)–STAT3 pathway. Notably, STAT3 silencing also inhibited ZDHHC4 expression. This study revealed that GSK3β palmitoylation mediated by ZDHHC4 improved the stemness of TMZ-resistant GBM by activating the EZH2–STAT3 signaling axis, providing a new theoretical basis for further understanding the mechanism of TMZ resistance and recurrence after treatment.
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影响因子：
4.4
作者：
Majewska E;Szeliga M
通讯作者：
Szeliga M
影响因子：
37.3
作者：
Beier D;Schulz JB;Beier CP
通讯作者：
Beier CP
影响因子：
5.6
作者：
D'Mello SR
通讯作者：
D'Mello SR
影响因子：
5.7
作者：
Domoto T;Pyko IV;Furuta T;Miyashita K;Uehara M;Shimasaki T;Nakada M;Minamoto T
通讯作者：
Minamoto T
影响因子：
48
作者：
Gonzalez-Perez A;Perez-Llamas C;Deu-Pons J;Tamborero D;Schroeder MP;Jene-Sanz A;Santos A;Lopez-Bigas N
通讯作者：
Lopez-Bigas N