PTB-AS, a Novel Natural Antisense Transcript, Promotes Glioma Progression by Improving PTBP1 mRNA Stability with SND1
Liyuan Zhu1, Qunfang Wei1, Yingjiao Qi1
1State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
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' 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' 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' UTR with the assistance of SND1, could significantly promote gliomagenesis.
Insights
A novel noncoding RNA, PTB-AS, promotes glioma growth by stabilizing PTBP1 mRNA. This mechanism, involving SND1 and miR-9, offers new insights into glioma progression and potential therapeutic targets.
Area of Science:
- Neuro-oncology
- Molecular Biology
- RNA Biology
Background:
- Glioma is a highly recurrent and lethal primary brain malignancy.
- Understanding glioma's molecular mechanisms is crucial for developing effective treatments.
- Poly-pyrimidine tract binding protein (PTBP1) is implicated in gliomagenesis, but its regulatory mechanisms are unclear.
Purpose of the Study:
- To identify novel regulatory mechanisms of PTBP1 expression in glioma.
- To investigate the role of a newly discovered natural antisense noncoding RNA, PTB-AS, in glioma.
- To elucidate the functional impact of PTB-AS on glioma cell proliferation and migration.
Main Methods:
- Correlation analysis of PTB-AS and PTBP1 mRNA expression.
- In vivo and in vitro assays to assess glioma cell proliferation and migration.
- RNA immunoprecipitation and mRNA stability assays to determine PTBP1 regulation by PTB-AS.
- Investigation of the roles of staphylococcal nuclease domain-containing 1 (SND1) and miR-9 in the PTB-AS/PTBP1 interaction.
Main Results:
- PTB-AS expression positively correlated with PTBP1 mRNA levels in glioma.
- PTB-AS significantly promoted glioma cell proliferation and migration.
- PTB-AS directly binds to the 3' UTR of PTBP1 mRNA, enhancing its stability.
- SND1 facilitated the binding of PTB-AS to PTBP1 mRNA, and PTB-AS masked the miR-9 binding site on PTBP1 mRNA.
Conclusions:
- PTB-AS is a novel natural antisense noncoding RNA that promotes gliomagenesis.
- PTB-AS stabilizes PTBP1 mRNA through direct binding to its 3' UTR, with SND1 assisting this interaction.
- PTB-AS promotes glioma progression by upregulating PTBP1 levels, potentially by inhibiting miR-9-mediated repression.
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