METTL14-Mediated M(6)A Modification of LINC01094 Induces Glucose Metabolic Reprogramming in Breast Cancer by Recruiting the PKM2/JMJD5 Complex.

Tumor cells reprogram their energy metabolism patterns to meet the needs of rapid growth and metastasis. The underlying mechanisms of long noncoding RNAs (lncRNAs) in glucose metabolism remodeling in breast cancer (BC) are still not well understood. Herein, the expression of a tumorigenic lncRNA, LINC01094 are demonstrated that, is significantly increased in BC tissues and is associated with poorer patient survival. METTL14-mediated m(6)A modification stabilized LINC01094 by recruiting the reader protein IGF2BP2, which contributed to the upregulation of LINC01094 expression in BC. Gain- and loss-of-function assays validated that LINC01094 triggered a switch in glucose metabolism from mitochondrial respiration to glycolysis, promoting BC progression both in vitro and in vivo. LINC01094 promoted the dimeric assembly and nuclear translocation of PKM2 by acting as a "molecular scaffold" for the PKM2/JMJD5 complex. This, in turn, facilitated energy metabolic reprogramming and cell proliferation induced by HIF1-α/β-catenin. Furthermore, the therapeutic potential of LINC01094 is evaluated through the administration of the PKM2 activator TEPP-46 in mouse xenografts. These findings highlight the critical roles of LINC01094 in cellular glucose metabolism and tumorigenesis in BC, suggesting that it is a potential therapeutic target.