Abstract
Transcribed ultraconserved regions (T-UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T-UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T-UCR in gliomas and mechanistically define a novel RNA-RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR-376 cluster. This includes the positive regulation of primary microRNA (pri-miRNA) cleavage and an enhanced A-to-I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR-376-regulated genes, including the transcriptional coregulators RING1 and YY1-binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower-grade gliomas, highlighting the importance of T-UCRs in cancer pathophysiology.
Original language | English |
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Pages (from-to) | 648-664 |
Number of pages | 17 |
Journal | Molecular oncology |
Volume | 16 |
Issue number | 3 |
Early online date | 3 Nov 2021 |
DOIs | |
Publication status | Published - Feb 2022 |
Keywords
- A-to-I editing
- glioma
- miR-376
- noncoding RNA
- pri-miRNA biogenesis
- T-UCR
- NONCODING RNA
- RYBP INTERACTS
- EXPRESSION
- MICRORNAS
- APOPTOSIS
- PROVIDES