PTRF/Cavin-1 as a Novel RNA-Binding Protein Expedites the NF-κB/PD-L1 Axis by Stabilizing lncRNA NEAT1, Contributing to Tumorigenesis and Immune Evasion in Glioblastoma

Abstract

BackgroundImmunotherapy, especially checkpoint inhibitors targeting PD-1 or PD-L1, has revolutionized cancer therapy. However, PD-1/PD-L1 inhibitors have not been investigated thoroughly in glioblastoma (GBM). Studies have shown that polymerase 1 and transcript release factor (PTRF/Cavin-1) has an immune-suppressive function in GBM. Thus, the relationship between PTRF and PD-L1 and their role in immune suppression requires further investigation in GBM.MethodsWe used public databases and bioinformatics analysis to investigate the relationship between PTRF and PD-L1. We next confirmed the predicted relationship between PTRF and PD-L1 in primary GBM cell lines by using different experimental approaches. RIP-Seq, RIP, ChIP, and qRT-PCR were conducted to explore the molecular mechanism of PTRF in immunosuppression.ResultsWe found that PTRF stabilizes lncRNA NEAT1 to induce NF-κB and PD-L1 and promotes immune evasion in GBM. PTRF was found to correlate with immunosuppression in the public GBM databases. PTRF increased the level of PD-L1 in primary cell lines from GBM patients. We carried out RIP-Seq of GBM cells and found that PTRF interacts with lncRNA NEAT1 and stabilizes its mRNA. PTRF also promoted the activity of NF-κB by suppressing UBXN1 expression via NEAT1 and enhanced the transcription of PD-L1 through NF-κB activation. Finally, PTRF promoted immune evasion in GBM cells by regulating PD-1 binding and PD-L1 mediated T cell cytotoxicity.ConclusionsIn summary, our study identified the PTRF-NEAT1-PD-L1 axis as a novel immune therapeutic target in GBM.

Molecular Interactions of the Long Noncoding RNA NEAT1 in Cancer

“…Specific proteins are responsible for the stability of NEAT1, including HuR, LIN28B, ALKBH5, PTRF, ALYREF, and SRSF1 [ 158 , 161 , 162 , 163 , 164 , 165 ]. Specifically, HuR and LIN28B can promote ovarian cancer progression via stabilizing NEAT1 [ 161 , 164 ].…”

“…Specifically, HuR and LIN28B can promote ovarian cancer progression via stabilizing NEAT1 [ 161 , 164 ]. In glioblastoma, PTRF can increase the stability of NEAT1 to promote cancer metastasis [ 165 ]. In addition, ALKBH5-stabilized NEAT1 can significantly suppress hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in glioblastoma [ 163 ].…”

Identification of Prognostic Signature of Necroptosis-Related lncRNAs and Molecular Subtypes in Glioma

“…NEAT1 activates NF- κ B and PD-L1 to promote immune evasion by interacting with PTRF in glioblastoma [ 17 ] (p1) . On the other hand, numerous studies indicated that lncRNAs could also regulate necroptosis by acting as competitive endogenous RNA and influencing target gene expression.…”

The role of LncRNAs in tumor immunotherapy

“…By inhibiting UBXN1 expression via NEAT1, PTRF enhanced PD-L1 transcription through promoting NF-κB activity. Finally, PTRF promoted immune escape of GBM cells though regulating PD-1 binding and PD-L1 mediated T cell toxicity [ 124 ].…”