PTB-AS, a Novel Natural Antisense Transcript, Promotes Glioma Progression by Improving PTBP1 mRNA Stability with SND1

Abstract

Glioma, the most common primary malignancy in the brain, has high recurrence and lethality rates, and thus, elucidation of the molecular mechanisms of this incurable disease is urgently needed. Poly-pyrimidine tract binding protein (PTBP1, also known as hnRNP I), an RNA-binding protein, has various mechanisms to promote gliomagenesis. However, the mechanisms regulating PTBP1 expression are unclear. Herein, we report a novel natural antisense noncoding RNA, PTB-AS, whose expression correlated positively with PTBP1 mRNA. We found that PTB-AS significantly promoted the proliferation and migration in vivo and in vitro of glioma cells. PTB-AS substantially increased the PTBP1 level by directly binding to its 3 0 UTR and stabilizing the mRNA. Furthermore, staphylococcal nuclease domain-containing 1 (SND1) dramatically increased the binding capacity between PTB-AS and PTBP1 mRNA. Mechanistically, PTB-AS could mask the binding site of miR-9 in the PTBP1-3 0 UTR; miR-9 negatively regulates PTBP1. To summarize, we revealed that PTB-AS, which maintains the PTBP1 level through extended base pairing to the PTBP1 3 0 UTR with the assistance of SND1, could significantly promote gliomagenesis.

The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization

“…This lncRNA is partially antisense to BACE1, a gene encoding the β-site amyloid precursor protein cleaving enzyme 1, which plays a crucial role in the pathophysiology of Alzheimer’s disease [ 42 ]. Interestingly, it has been shown that lncRNA BACE1-AS is markedly up-regulated in brain samples from patients with Alzheimer’s disease and promotes the stability of the BACE1 transcript [ 43 ]. The lncRNA BACE1-AS regulates the expression of its sense partner through a synergistic mechanism that includes prevention of miRNA-induced mRNA decay and translational repression.…”

“…The lncRNA BACE1-AS regulates the expression of its sense partner through a synergistic mechanism that includes prevention of miRNA-induced mRNA decay and translational repression. Specifically, miR-485-5p and BACE1-AS share a common binding site in the sixth exon of BACE1 mRNA transcript, and thus binding of BACE1-AS to this site avoids the interaction of miR-485-5p , hindering the translational repression and destabilization of BACE1 mRNA by miR-485-5p , and eventually elevating BACE1 levels [ 43 ].…”

PTBP1‐targeting microRNAs regulate cancer‐specific energy metabolism through the modulation of PKM1/M2 splicing

“…We and others have previously shown the uneven organ distribution of PTBP1-or PKM-targeting miRNAs under physiological conditions, as well as their downregulation in certain cancers. 24,25,[40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] Notably, the introduction of PTBP1-targeting miRNAs induced the switch of PKM isoforms from the cancer-dominant PKM2 to PKM1. 24,25,[40][41][42][43] Nowadays, microarray data on the distribution of miRNAs across human tissues are freely available online (https://ccbweb.cs.uni-saarl and.de/tissu eatla s/).…”

“…Another representative brain-specific miRNA, MIR9-5p, promotes differentiation of neuronal cells from retinal stem cells through downregulation of PTBP1; 63 the association of MIR9-5p and PTBP1 was also reported in glioma. 45 A natural antisense transcript (PTB-AS) stabilizes the expression of PTBP1, preventing the binding of MIR9-5p to the PTBP1 3′UTR. 45 Note: Gene names are described according to the Gene Nomenclature Committee of Human Genome Organization (https://www.genen ames.org/).…”

“…45 A natural antisense transcript (PTB-AS) stabilizes the expression of PTBP1, preventing the binding of MIR9-5p to the PTBP1 3′UTR. 45 Note: Gene names are described according to the Gene Nomenclature Committee of Human Genome Organization (https://www.genen ames.org/). The miRNA terminology used follows the proposed miRNA nomenclature guidelines.…”