Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis

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Abstract

Rationale: Non-small cell lung cancer (NSCLC) is a deadly disease with a hallmark of aberrant metabolism. The mechanism of glycolysis associated lncRNA underlying the aggressive behaviors of NSCLC is poorly understood. Methods: The expression level of AC020978 in NSCLC was measured by quantitative real-time PCR and fluorescence in situ hybridization (FISH) assay. The biological role of AC020978 in cell proliferation and aerobic glycolysis was determined by functional experiments in vitro and in vivo. The transcription of AC020978 was assessed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assay. RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the interaction protein with AC020978. Western blotting, in situ proximity ligation assay (PLA), and co-immunoprecipitation (co-IP) were performed to reveal the potential mechanism of AC020978. Results: The present study indicated that AC020978 was upregulated in NSCLC, significantly correlated with advanced TNM stage and poor clinical outcomes, representing as an independent prognostic predictor. Functional assays revealed AC020978's role in promoting cell growth and metabolic reprogramming. Moreover, AC020978 was an upregulated lncRNA under glucose starvation as well as hypoxia conditions, and directly transactivated by HIF-1α. Mechanistic investigations identified that AC020978 directly interacted with Pyruvate kinase isozymes M2 (PKM2) and enhanced PKM2 protein stability. Besides, this study uncovered that AC020978 could promote the nuclear translocation of PKM2 and regulate PKM2-enhanced HIF-1α transcription activity. Conclusions: Together, these data provided evidence that AC020978 conferred an aggressive phenotype to NSCLC and was a poor prognosticator. Targeting AC020978 might be an effective therapeutic strategy for NSCLC.

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