The transcribed ultraconserved region uc.160+ enhances processing and A-to-I editing of the miR-376 cluster: hypermethylation improves glioma prognosis

M. Soler, V. Davalos, A. Sanchez-Castillo, C. Mora-Martinez, F. Setien, E. Siqueira, M.C. de Moura, M. Esteller, S. Guil*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

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 languageEnglish
Pages (from-to)648-664
Number of pages17
JournalMolecular oncology
Volume16
Issue number3
Early online date3 Nov 2021
DOIs
Publication statusPublished - 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

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