Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival
Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival
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DOI：
10.1038/s41389-019-0134-2
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发表时间：
2019-04
期刊：
影响因子：
6.2
通讯作者：
Jing Wei;Qi Yang;Jing Shi;B. Shi;Meiju Ji;P. Hou
中科院分区：
文献类型：
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作者：
Jing Wei;Qi Yang;Jing Shi;B. Shi;Meiju Ji;P. Hou
H/ACA核糖核蛋白（RNP）复合物非核心亚基NAF 1是H/ACA RNP成熟过程中不可或缺的因子，其功能之一是调节核糖体的生物合成。然而，NAF 1在包括胶质瘤在内的人类癌症中的具体生物学作用和确切机制仍不清楚。在这项研究中，我们发现NAF 1在胶质瘤中相对于正常脑组织高表达，并证明NAF 1表达增加与患者生存率低密切相关。进一步的研究发现NAF 1受c-Myc、NRF 2和端粒酶逆转录酶（telomerase reverse transcriptase，TERT）的转录调控，这些分子是与胶质瘤恶性进展相关的关键分子。此外，我们证明NAF 1是一个功能性癌基因，在胶质瘤细胞通过促进细胞生长，在体外和体内，生存，迁移和侵袭。从机制上讲，NAF 1通过增强40 S亚基组装和蛋白质合成（包括c-Myc、NRF 2、TERT、POLR 1A和POLR 2A），作为细胞生长和侵袭的限速控制器。这些分子反过来又增强了NAF 1的转录和翻译，从而在它们之间形成正反馈环，促进胶质瘤细胞的恶性表型。此外，我们的数据还表明，NAF 1缺失可以触发核糖体应激，不仅损害核糖体生物合成，而且通过阻断MDM 2重新激活p53信号转导。综上所述，我们证明NAF 1通过调节核糖体组装和蛋白质合成促进胶质瘤的发生和发展，并预测NAF 1可能是胶质瘤潜在的治疗靶点和有价值的预后生物标志物。
The H/ACA ribonucleoprotein (RNP) complex noncore subunit NAF1 is an indispensable factor during H/ACA RNP maturation, and one of the widely known functions of H/ACA RNP is modulating ribosome biosynthesis. However, the specific biological role and exact mechanism of NAF1 in human cancers including glioma remain largely unclear. In this study, we found that NAF1 was highly expressed in gliomas relative to normal brain tissues, and demonstrated that increased expression of NAF1 was strongly correlated with poor patient survival. Further studies revealed that NAF1 was transcriptionally regulated by c-Myc, NRF2, and telomerase reverse transcriptase (TERT), which are the key molecules associated with malignant progression of gliomas. Moreover, we demonstrated that NAF1 was a functional oncogene in glioma cells through promoting cell growth in vitro and in vivo, survival, migration, and invasion. Mechanistically, NAF1 acted as a rate-limiting controller of cell growth and invasiveness through enhancing 40S subunit assembly and protein synthesis including c-Myc, NRF2, TERT, POLR1A, and POLR2A. These molecules in turn enhanced the transcription and translation of NAF1, thereby forming positive feedback loops between them to promote malignant phenotypes of glioma cells. In addition, our data also showed that NAF1 depletion could trigger ribosome stress, not only impairing ribosomal biosynthesis but also reactivating p53 signaling via blocking MDM2. Taken together, we demonstrated that NAF1 promotes the tumorigenesis and progression of glioma through modulating ribosome assembly and protein synthesis, and predicted that NAF1 may be a potential therapeutic target and valuable prognostic biomarker in gliomas.