NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma
NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma
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NFAT2-HDAC1 信号传导导致胶质母细胞瘤的恶性表型
DOI：
10.1093/neuonc/noz136
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发表时间：
2020-01-01
期刊：
影响因子：
15.9
通讯作者：
Han, Sheng
中科院分区：
文献类型：
--
作者：
Song, Yifu;Jiang, Yang;Han, Sheng
背景。据报道，在几种人类癌症中，活化 T 细胞核因子 (NFAT) 通路的失调。特别地，NFAT2参与肿瘤细胞的恶性转化并被鉴定为癌基因。然而，NFAT2 在胶质母细胞瘤 (GBM) 中的作用很大程度上未知。在分子脑肿瘤数据存储库和癌症基因组图谱 (TCGA) 数据库以及临床样本中检查了 NFAT2 的表达和预后价值。评估 NFAT2 沉默或过表达对胶质瘤干细胞 (GSC) 活力、侵袭和自我更新的体外以及体内致瘤性的功能影响。研究 NFAT2 的下游靶点。结果。高 NFAT2 表达与间充质 (MES) 亚型和复发性 GBM 显着相关，并预测较差的生存率。 NFAT2 沉默可抑制体内外富含 MES GSC 球体的侵袭和克隆形成。 NFAT2 过表达促进 GSC 的肿瘤生长和 MES 分化。 TCGA 数据库检索显示组蛋白脱乙酰酶 1 (HDAC1) 表达与 NFAT2 显着相关。 NFAT2 调节 HDAC1 的转录活性。在 NFAT2 敲除的 GSC 中拯救 HDAC1 可部分恢复肿瘤生长和 MES 表型。 NFAT2 和 HDAC1 表达缺失导致核因子 kappaB (NF-kappa B) 过度乙酰化，从而抑制 NF-kappa B 依赖性转录活性。结论。我们的研究结果表明，NFAT2-HDAC1 通路可能在 GSC 恶性表型的维持和促进 MES 转变中发挥重要作用，为 GBM 的治疗提供潜在的分子靶点。
Background. Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown.Methods. The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo.The downstream target of NFAT2 was investigated.Results. High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-kappa B), which inhibits NF-kappa B-dependent transcriptional activity.Conclusion. Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.