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.
Highlights
Gliomas, which account for about 2–4% of all systemic malignant tumors, comprise about 30% of all brain tumors and central nervous system tumors, and 75% of all malignant brain tumors[1]
We used The Cancer Genome Atlas (TCGA) dataset to evaluate the association of NAF1 expression with patient survival after excluding the patients over the age of 70 years, and found that there was a strong relationship between increased expression of NAF1 and poor overall survival in the patients with low-grade gliomas (LGGs) (P = 0.0296) (Fig. 1d), but not in those with glioblastomas (GBMs) (Fig. 1e)
NAF1 is required for the assembly of H/ACA box small nucleolar RNP12, and there is evidence showing the importance of Naf1p in cell growth in yeast[28]
Summary
Gliomas, which account for about 2–4% of all systemic malignant tumors, comprise about 30% of all brain tumors and central nervous system tumors, and 75% of all malignant brain tumors[1]. The mammalian H/ACA box ribonucleoproteins (RNPs) consist of only one of the 100–200 diverse box H/ ACA small nucleolar RNA (snoRNA) and the evolutionary conserved four key proteins including NAP57, NOP10, NHP2 (forming the core trimer), and GAR1. They perform several basic biological functions, such as protein synthesis, gene expression, and chromosome stability[9,11]. NAF1, an H/ACA box RNP assembly chaperone, is a factor necessary for H/ACA snoRNP maturation and ribosome biosynthesis in mammalian cells[12] Among these RNA biogenesis factors, NAF1 may be unique in that it is required at full dosage for telomerase and telomere maintenance in the process of pulmonary fibrosis–emphysema[13]. There is evidence showing that single nucleotide polymorphisms (SNPs) in NAF1 are associated with cancer risk probably through affecting telomere length[14,15]; to our knowledge, no studies are available to define its role in human cancers, especially in gliomas
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