The Role of Long Noncoding RNAs APTR and LINC00152 in Gliomas
Takao Real Karia, Bruno, Biochemistry and Molecular Genetics - School of Medicine, University of Virginia
Takao real karia, Bruno, Medicine Graduate-msg, University of Virginia
Since the advent of high-throughput sequencing methods, long non-coding RNAs (lncRNAs) have been emerging as important players in physiological and pathological conditions. Among them, APTR (Alu-mediated p21 transcriptional regulator) is a lncRNA upregulated in tumors. This RNA regulates the cell cycle by recruiting the PRC2 protein complex (Polycomb Repressive Complex 2) to the promoter region of p21 gene, inducing its suppression. In addition, APTR and p21 expressions are anti-correlated in glioblastoma patient samples. Exploring the possibility that APTR interact with other genomic sites and recruit other binding proteins, the present work shows that APTR interacts with more than 2,000 genomic loci. By intersecting a publicly available EZH2 dataset, I found that 115 DNA APTR bound sites are marked with EZH2. Moreover, a microarray study revealed that APTR regulates the expression of 274 genes, of which 43 are nearby an APTR associated DNA. Another pull-down assay uncovered 70 potential binding partners for APTR. BRD7 (Bromodomain-containing protein 7) and NFIC (Nuclear Factor I C) RNA Immunoprecipitation confirmed APTR interaction with these two transcription factors.
This study also identified another lncRNA, LINC00152, as upregulated in 12 types of tumor, including glioblastomas. In addition, its upregulation is indicative of worse prognosis in 9 cancer types. LINC00152 knockdown decreases GBM cells anchorage-independent proliferation and cellular invasion. While overexpression induces these phenotypes. RNA-seq experiment revealed that LINC00152 controls the expression of genes involved in epithelial-to-mesenchymal transition. A protein bound stem-loop at the 3’ end of LINC00152, identified by PARIS, Ribo-seq and secondary structure prediction data, is sufficient to increase invasion of glioblastoma cell lines. Overexpression of LINC00152 stem-loop mutants suggests that stem formation in the hairpin is essential for LINC00152 function.
Finally, because of their high expression in glioblastomas, APTR and LINC00152 may serve as biomarkers for development and progression of patients with this cancer. In addition, since it is upregulated in 12 different tumors and its upregulation indicates worse outcomes in 9 of them, LINC00152 may serve as a biomarker for patient prognosis.
PHD (Doctor of Philosophy)
long noncoding RNA, cancer, glioma, APTR, LINC00152, cell cycle, cell invasion