LINC01116 promotes glycolysis by up-regulating HIF-1α via YBX1-mediated dual mechanism in lung cancer

Hypoxia is a hallmark of the lung cancer microenvironment, activating hypoxia-inducible factor 1α (HIF-1α[jls-end-space/]; encoded by HIF1A) to trigger adaptive responses that support tumor cell survival. The oncogenic long noncoding RNA LINC01116, identified as a hypoxia-associated molecule by gene set enrichment analysis, promoted glycolysis and proliferation in lung cancer. Functional assays revealed that LINC01116 enhanced glucose consumption, lactate production, and hexokinase 2 expression under hypoxic conditions in a HIF-1α[jls-end-space/]-dependent manner, then enhanced cell proliferation through glycolysis. Mechanistically, LINC01116 enhanced HIF-1α signaling via a Y-box binding protein 1 (YBX1)-mediated dual mechanism. First, LINC01116 promoted the direct interaction between YBX1 and HIF1A mRNA, facilitating HIF-1α protein synthesis under hypoxic conditions. Second, LINC01116 upregulated the deubiquitinase ubiquitin-specific peptidase 22 (USP22) by recruiting YBX1 to USP22 mRNA, which in turn reduced ubiquitin-proteasome-mediated degradation of HIF-1α[jls-end-space/]. Deletion-mapping analyses indicated that the interaction between YBX1 and LINC01116 was mediated through two distinct regions of LINC01116 (1-400 nt and 701-1085 nt). Additionally, the binding of YBX1 to LINC01116, HIF1A mRNA, and USP22 mRNA was mediated through its cold shock domain. In vivo, overexpression of LINC01116 promoted tumor growth, which could be partially reversed by glycolysis inhibition. These findings uncover a novel LINC01116-YBX1-USP22/HIF-1α regulatory axis that sustains glycolysis and proliferation under hypoxic conditions, offering new insights into metabolic reprogramming in lung cancer and potential therapeutic targets for overcoming metabolic vulnerabilities.