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首页> 美国卫生研究院文献>Theranostics >Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas
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Chromatin Remodeling Factor LSH is Upregulated by the LRP6-GSK3β-E2F1 Axis Linking Reversely with Survival in Gliomas

机译：LRP6-GSK3β-E2F1轴与胶质瘤的存活成反比从而上调了染色质重塑因子LSH。

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The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3β (GSK-3β), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3β increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3β signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3β/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma.
机译：在胶质瘤中，基于信号通路的染色质修饰分层可比基于单独形态学的分类方案更可靠地预测临床结果。在这里我们报告了染色质重塑因子淋巴样解旋酶（LSH）在神经胶质瘤中的作用。在I至III级星形胶质瘤和IV级胶质母细胞瘤中，LSH在所有病例中几乎完全表达，并与星形细胞瘤和胶质母细胞瘤患者的星形细胞瘤进展和不良预后密切相关。 LSH的异位表达促进肿瘤形成。星形细胞瘤和胶质母细胞瘤中转录因子E2F1的上调与神经胶质瘤的进展有关，并与LSH的表达有关。染色质免疫沉淀（ChIP）分析表明，转录因子E2F1被募集到LSH的启动子区域，而E2F1的消耗会降低LSH的表达和细胞生长。此外，糖原合酶激酶3β（GSK-3β），一种完整的E2F1复合物，也在星形细胞瘤中高表达，并与星形细胞瘤的进展和星形细胞瘤和胶质母细胞瘤患者的不良预后有关。抑制GSK3β可增加E2F1对LSH启动子的富集，进而增加LSH表达。脂蛋白受体相关蛋白6（LRP6），GSK3β信号通路的上游调节剂，在神经胶质瘤中高表达。降低LRP6的表达通过减少E2F1向LSH启动子的募集而降低LSH表达，从而抑制细胞生长。两者合计，这项研究揭示了证据证明上调的促进胶质瘤的机制。 LSH表达与神经胶质瘤中LPR6 /GSK3β/ E2F1轴激活之间的机制联系说明了LSH在恶性星形细胞瘤和胶质母细胞瘤中的新作用。

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