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Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival.

ABSTRACT: 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.

SUBMITTER: Wei J

PROVIDER: S-EPMC6443650 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival.

Wei Jing J Yang Qi Q Shi Jing J Shi Bingyin B Ji Meiju M Hou Peng P

Oncogenesis 20190401 4

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 corre ...[more]

PMID: 30936423

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Project description:BackgroundMethyltransferase-like 3 (METTL3) expression could be found in various normal and cancerous tissues. As of now, the clinical significance of METTL3 expression in human pancreatic cancer (PC) tissues still remains to be understood. Our present study aims to investigate the prognostic value and clinical implications of METTL3 expression in PC tissues.MethodsThe TCGA, GTEx, and GEO public databases were used to study the mRNA expression level of the m6A family members and its relationship among PC tissues and normal pancreatic tissue. The immunohistochemistry was used to analyze the difference of METTL3 expression between cancer tissues and adjacent normal tissues. The prognostic value was evaluated by using the Log-rank survival analysis and Cox model analysis. PAAD samples from TCGA and GEO databases were used to perform the immune infiltration analysis and gene set enrichment analysis based on the genes that were highly correlated with METTL3.ResultsBased on the analysis of TCGA, GTEx, and GEO public database, we found that the m6A family members showed a higher correlation in PC tissues compared to normal pancreatic tissues, and the mRNA expression level of the m6A family members showed a significant difference between PC tissues and adjacent normal tissues. Moreover, scRNA-seq data indicated that METTL3 showed a higher expression level in malignant epithelial cells. Our immunohistochemistry results also confirmed that the intensity of METTL3 immunostaining in PC tissues was significantly higher than that in adjacent normal tissues (P = 0.015). The overall survival (OS) of PC patients with high expression of METTL3 protein were significantly poorer than those with low expression of METTL3 protein (HR = 1.788, 95% CI 1.071-2.984, P = 0.026). Further analysis of PC data from the database showed that METTL3 expression was associated with a variety of tumor-infiltrating immune cells and was involved in m6A modification and metabolism in PC tissues.ConclusionIncreased METTL3 expression at the protein level could be found in PC tissues, suggesting that the METTL3 expression was involved in the progression of PC and could serve as an important marker for prognostic prediction of this malignancy.

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Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival.

Publications

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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