Abstract
Research over the past decade has suggested important roles for pseudogenes in glioma. This study aimed to show that pseudogene PRELI domain-containing 1 pseudogene 6 (PRELID1P6) promotes glioma progression. Aberrant expression of genes was screened using The Cancer Genome Atlas database. We found that mRNA level of PRELID1P6 was highly upregulated in glioma and was associated with a shorter survival time. Functional studies showed that the knockdown of PRELID1P6 decreased cell proliferation, sphere formation, and clone formation ability and blocked the cell cycle transition at G0/G1, while overexpression of PRELID1P6 had the opposite effects. Mechanistically, knockdown of PRELID1P6 changed the cellular localization of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) from nucleus to cytoplasm, which promoted ubiquitin-mediated degradation of hnRNPH1. RNA-sequence and gene set enrichment analysis suggested that knockdown of PRELID1P6 regulates the apoptosis signaling pathway. Western blotting showed that PRELID1P6 increased TRF2 expression by hnRNPH1-mediated alternative splicing effect and activated the Akt/mTOR pathway. Furthermore, Akt inhibitor MK2206 treatment reversed the oncogenic function of PRELID1P6. PRELID1P6 was also found to be negatively regulated by miR-1825. Our result showed that PRELID1P6 promotes glioma progression through the hnHNPH1-Akt/mTOR pathway. These findings shed new light on the important role of PRELID1P6 as a novel oncogene for glioma.
Highlights
Gliomas are the most common type of primary malignant brain tumor in adults
We found that the mRNA level of PRELID1P6 was significantly higher in glioma tissues than that in adjacent normal tissues (Fig. 1B), a finding that was further confirmed by a cohort containing 34 cases of paired fresh glioma and adjacent nontumorous brain tissues from Sun Yat-sen University Cancer Center
According to the expression of PRELID1P6 in the glioma cell lines (Fig. 1F), two shRNAs targeting PRELID1P6 and a control sequence were transfected into U251 and U373 cell lines, while a lentiviral PRELID1P6 construct and control were stably transfected into U138 and LNZ308 cell lines. qRT-PCR confirmed that the expression of PRELID1P6 was significantly downregulated or upregulated in glioma cell lines (Fig. 2A, B)
Summary
Gliomas are the most common type of primary malignant brain tumor in adults. They are associated with a short survival, and direct repercussions on the quality of life and cognitive functions [1, 2]. Further advancements in technologies to identify new biomarkers to improve the understanding of the regulation of cell processes and treatment of glioma are needed. Noncoding RNAs were reported to be involved in the pathogenesis of cancer with diverse functions and mechanisms [11, 12]. With advancements in next-generation sequencing, pseudogenes were found to play critical roles in transcriptional and posttranscriptional regulation in cancer cells [14]. Research on pseudogenes and deeper understanding of their biological functions are important to decipher the etiology of cancer, and facilitate new approaches for cancer screening, prevention, and treatment
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