DYRK1A activates NFATC1 to increase glioblastoma migration.
DYRK1A activates NFATC1 to increase glioblastoma migration.
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DYRK1A 激活 NFATC1 以增加胶质母细胞瘤迁移
DOI：
10.1002/cam4.4159
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发表时间：
2021-09
期刊：
影响因子：
4
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Liu H;Sun Q;Chen S;Chen L;Jia W;Zhao J;Sun X
胶质母细胞瘤（GBM）是最具侵袭性的胶质瘤，容易对化疗和放疗产生耐药性；因此，胶质母细胞瘤患者复发率高，1年生存率低。此外，胶质母细胞瘤的发病机制是复杂的，很大程度上是未知的，可用的治疗是有限的。在这里，我们发现DYRK1A在GBMs中调节NFATC1的基本作用。我们发现DYRK1A在胶质瘤和胶质母细胞瘤细胞中高表达，其表达与NFATC1呈正相关。此外，抑制DYRK1A促进了GBM细胞中NFATC1的降解，并通过降低NFATC1靶向基因的表达，降低荧光素酶的活性，大幅降低了NFATC1的反激活，反之亦然。然而，DYRK1A对NFATC2具有相反的作用。最重要的是，我们的数据表明DYRK1A抑制可减少胶质母细胞瘤的迁移。通过竞争性地阻断NFATC1上的DYRK1A激酶活性，从NFATC1的DYRK1A靶向基元中衍生的多肽明显地破坏了NFATC1蛋白的稳定性，并损害了胶质母细胞瘤的迁移。我们认为NFATC1稳定性的恢复是大部分胶质瘤的一个关键致癌事件，多肽对DYRK1A的药理学抑制可能代表了GBM的一种有希望的治疗干预。我们发现DYRK1A蛋白通过影响GBM细胞中NFATc1的降解和反激活，与NFATc1蛋白呈正相关。DYRK1A抑制或源于DYRK1A靶向NFATc1基序的多肽，明显破坏了NFATc1蛋白的稳定，并损害了胶质母细胞瘤的迁移。我们提出，NFATc1稳定性的恢复是大部分胶质瘤的一个关键致癌事件，多肽药物抑制DYRK1A可能代表了对NFATc1依赖性GBM的有希望的治疗干预。
Glioblastoma (GBM) is the most aggressive glioma, and is prone to develop resistance to chemotherapy and radiotherapy; hence, patients with glioblastoma have a high recurrence rate and a low 1‐year survival rate. In addition, the pathogenesis of glioblastoma is complex and largely unknown, and the available treatments are limited. Here, we uncovered a fundamental role of DYRK1A in regulating NFATC1 in GBMs. We found that DYRK1A was highly expressed in glioma and glioblastoma cells, and its expression was positively correlated with that of NFATC1. Moreover, inhibition of DYRK1A promoted NFATC1 degradation in GBM cells and sharply reduced the transactivation of NFATC1, not only by decreasing the expression of NFATC1‐targeted genes, but also by reducing the luciferase activity, and vice versa. However, DYRK1A had the opposite effect on NFATC2. Most importantly, our data suggest that DYRK1A inhibition reduces glioblastoma migration. Polypeptides derived from the DYRK1A‐targeted motif of NFATC1, by competitively blocking DYRK1A kinase activity on NFATC1, clearly destabilized NFATC1 protein and impaired glioblastoma migration. We propose that the recovery of NFATC1 stability is a key oncogenic event in a large proportion of gliomas, and pharmacological inhibition of DYRK1A by polypeptides could represent a promising therapeutic intervention for GBM. We found that DYRK1A protein was positively correlated with that of NFATc1 through affecting NFATc1 degradation and transactivation in GBM cells. DYRK1A inhibition or polypeptide derived from DYRK1A‐targeted motif of NFATc1, clearly destabilized NFATc1 protein and impaired glioblastoma migration. We propose that the recovery of NFATc1 stability is a key oncogenic event in a large proportion of gliomas and polypeptide pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for NFATc1‐dependent GBM.
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