lncRNA FGD5-AS1 is required for gastric cancer proliferation by inhibiting cell senescence and ROS production via stabilizing YBX1

BackgroundThe vast majority of lncRNAs have low expression abundance, which greatly limits their functional range and impact. As a high expression abundance lncRNA, FGD5-AS1's non-ceRNA biological function in cancer is unclear.MethodsRNA-seq studies and chromatin immunoprecipitation (Chip) assays were performed to identify ZEB1-regulated lncRNAs. RNA sequencing, RNA pulldown, RNA Immunoprecipitation assays, and rescue assays were conducted to explore the molecular mechanisms of FGD5-AS1 in GC.ResultsAs one of the most abundant lncRNAs in cells, FGD5-AS1 has been shown to be transcriptionally activated by ZEB1, thus closely related to epithelial-mesenchymal transition (EMT) signaling. Clinical analysis showed that FGD5-AS1 overexpression was clinically associated with lymph node metastasis, and predicted poor survival in GC. Loss-of-function studies confirmed that FGD5-AS1 knockdown inhibited GC proliferation and induced cisplatin chemosensibility, cell senescence, and DNA damage in GC cells. Mechanismically, FGD5-AS1 is a YBX1-binding lncRNA due to its mRNA contains three adjacent structural motifs (UAAUCCCA, ACCAGCCU, and CAGUGAGC) that can be recognized and bound by YBX1. And this RNA-protein interaction prolonged the half-life of the YBX1 protein in GC. Additionally, a rescue assay showed that FGD5-AS1 promotes GC by repressing cell senescence and ROS production via YBX1.ConclusionFGD5-AS1 is a cellular high-abundant lncRNA that is transcriptionally regulated by ZEB1. FGD5-AS1 overexpression promoted GC progression by inhibiting cell senescence and ROS production through binding and stabilizing the YBX1 protein. FGD5-AS1 is an EMT-related, cellularly abundant lncRNA. The expression of FGD5-AS1 is directly regulated by the transcription factor ZEB1.FGD5-AS1 overexpression was clinically associated with lymph node metastasis and a poor prognosis in GC.Knockdown of FGD5-AS1 causes senescence-associated secretory phenotypes, DNA damage, cisplatin chemosensibility, and growth inhibition in GC cells.FGD5-AS1 prolongs the half-life of the YBX1 protein by RNA-protein interaction. The UAAUCCCA, ACCAGCCU, and CAGUGAGC linear 8-mer motifs in the FGD5-AS1 transcript mediate the interaction between YBX1 and FGD5-AS1.FGD5-AS1 promotes GC proliferation by inhibiting cell senescence and ROS production in a YBX1-dependent manner.