BM supervised the overall research and revision of the manuscript. clinical samples was evaluated by quantitative real-time PCR assay and fluorescence in situ hybridization. The biological role of “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 on NSCLC cells were evaluated by functional experiments in vitro and in vivo. Moreover, RNA pull-down, mass spectrometry and Tretinoin RNA immunoprecipitation (RIP) assays were used to identify the protein interacted with “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338. Co-immunoprecipitation, in situ proximity ligation assays and western blotting were applied to define the potential downstream pathways of “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338. Results “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 was an upregulated glycolysis-associated lncRNA in NSCLC. Functional assays revealed that “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 was critical for promoting aerobic glycolysis and NSCLC progression. Mechanistic investigations showed that “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 directly bound with alpha-enolase (ENO1) and enhanced the proteins stability by modulating its degradation and ubiquitination. A positive correlation was observed between “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 and ENO1 in NSCLC, and ENO1 was subsequently confirmed to be responsible for the oncogenic role of “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338. Furthermore, “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 was capable of modulating ENO1/EGFR complex conversation and further activating EGFR-AKT signaling. Conclusions This study indicates that “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 confers an aggressive phenotype to NSCLC, and targeting it might be an effective therapeutic strategy. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02232-z. abundance, could promote glycolysis and oncogenesis by targeting ENO1 and guiding its histone modification pattern in colorectal cancer. Another group confirmed that lncRNA SNHG18 promoted glioma cell motility by disrupting the nucleocytoplasmic shuttling of ENO1 [28]. Consistent with the previous report, our results suggested that ENO1 was responsible for the oncogenic role of “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 in mediating NSCLC progression. ENO1 silencing weakened the exogenous “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338-induced metabolic shift in NSCLC cells. “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 also maintained ENO1 protein stabilization through decreasing ubiquitin-mediated degradation. Notably, we observed simultaneous Tretinoin upregulation and correlation of “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 and ENO1 in NSCLC tissues. ENO1 and “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 overexpression were strongly associated with poor prognosis in NSCLC patients, suggesting that “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 and ENO1 levels may predict patient outcome. In addition to its canonical functions in glycolysis, accumulating evidence revealed ENO1 as a multifunctional protein involved in regulating several signaling pathways [29]. A recent study reported that ENO1 promoted the self-renewal and malignant phenotype of lung cancer stem cells by affecting the AMPK/mTOR Tretinoin pathway [23]. Fu et al. [24] showed that ENO1 was involved in NSCLC glycolysis, proliferation, and metastasis through the FAK-mediated PI3K/AKT pathway. It is rather amazing Tretinoin that EGFR is the best-characterized receptor tyrosine kinase and EGFR signaling is among the most dysregulated molecular pathways in NSCLC [30]. Upon ligand binding to EGFR, the AKT signaling pathway will be activated, leading to enhanced glycolysis and oncogenic phenotypes in tumor cells [31]. Given the positive correlation of ENO1 and EGFR expression in NSCLC and their comparable functions in AKT pathway regulation, these reports inspired us to explore whether ENO1 might be an conversation partner of EGFR. Notably, a direct conversation between ENO1 and EGFR was observed by reverse co-IP, and native ENO1/EGFR protein complexes were visualized with PLA assays. Moreover, our data clearly showed that ENO1 positively regulated EGFR phosphorylation and thus activated downstream AKT kinase signaling. Previous studies revealed that Rabbit Polyclonal to TAS2R49 lncRNAs might act as a tumorigenic regulator by modulating signaling networks [32]. Apart from directly modulating ENO1 expression, we hypothesized that “type”:”entrez-nucleotide”,”attrs”:”text”:”AL355338″,”term_id”:”15787728″,”term_text”:”AL355338″AL355338 functions through the ENO1-mediated EGFR/AKT pathway.