DHHC protein family targets different subsets of glioma stem cells in specific niches
DHHC protein family targets different subsets of glioma stem cells in specific niches
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DHHC 蛋白家族针对特定生态位中的不同神经胶质瘤干细胞亚群
DOI：
10.1186/s13046-019-1033-2
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发表时间：
2019-01-18
影响因子：
11.3
通讯作者：
Fang, Zhiyou
中科院分区：
文献类型：
--
作者：
Chen, Xueran;Hu, Lei;Fang, Zhiyou
胶质母细胞瘤（GBM）包括不同的亚群，表现出明显的异质性和可塑性，导致基因组谱分析在指导针对这些肿瘤的精确医学方法的发展方面缺乏成功。因此，迫切需要研究不同GBM亚群的调控机制，并鉴定与GBM特异性小生境相关的新生物标志物和治疗靶点。DHHC蛋白家族与胶质瘤的恶性发展和进展密切相关。然而，这些蛋白质的可塑性GBM subsets.MethodsThis研究利用人脑胶质瘤原神经或间充质干细胞的作用仍不清楚。通过体外和体内测定研究DHHC蛋白对不同GBM亚群的作用（即，集落形成测定、流式细胞术测定、双重免疫荧光、蛋白质印迹和异种移植模型）。使用Western印迹、免疫共沉淀和液相色谱质谱-质谱分析来检测ZDHHC 18和ZDHHC 23在各种GBM亚型中的蛋白复合物，结果ZDHHC 18和ZDHHC 23能靶向不同GBM亚群的胶质瘤干细胞，并能调节胶质瘤干细胞的增殖和分化。这些亚型的细胞可塑性。此外，机制研究表明，ZDHHC 18和ZDHHC 23竞争性地与BMI 1 E3连接酶RNF 144 A相互作用，以调节BMI 1的多聚泛素化和积累。这些事件有助于过渡的胶质瘤干细胞在GBM和细胞生存的压力肿瘤microenvironment.ConclusionsOur工作突出的作用DHHC蛋白质的可塑性GBM子集，并揭示了BMI 1代表一个潜在的治疗靶点，为人类胶质瘤。
BackgroundGlioblastomas (GBM) comprise different subsets that exhibit marked heterogeneity and plasticity, leading to a lack of success of genomic profiling in guiding the development of precision medicine approaches against these tumors. Accordingly, there is an urgent need to investigate the regulatory mechanisms for different GBM subsets and identify novel biomarkers and therapeutic targets relevant in the context of GBM-specific niches. The DHHC family of proteins is associated tightly with the malignant development and progression of gliomas. However, the role of these proteins in the plasticity of GBM subsets remains unclear.MethodsThis study utilized human glioma proneural or mesenchymal stem cells as indicated. The effects of DHHC proteins on different GBM subsets were investigated through in vitro and in vivo assays (i.e., colony formation assay, flow cytometry assay, double immunofluorescence, western blot, and xenograft model). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to detect the protein complexes of ZDHHC18 and ZDHHC23 in various GBM subtypes, and explore the mechanism of DHHC proteins in targeting different subsets of GSCs in specific niches.ResultsZDHHC18 and ZDHHC23 could target the glioma stem cells of different GBM subsets in the context of their specific niches and regulate the cellular plasticity of these subtypes. Moreover, mechanistic investigations revealed that ZDHHC18 and ZDHHC23 competitively interact with a BMI1 E3 ligase, RNF144A, to regulate the polyubiquitination and accumulation of BMI1. These events contributed to the transition of glioma stem cells in GBM and cell survival under the stressful tumor microenvironment.ConclusionsOur work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.