METTL3-mediated m6A modification of LINC00520 confers glycolysis and chemoresistance in osteosarcoma via suppressing ubiquitination of ENO1

Chemoresistance remains the main obstacle limiting the treatment of osteosarcoma, seriously affecting the prognosis of adolescent patients with osteosarcoma. Recently, long non-coding RNAs (lncRNAs) were reported to be involved in chemoresistance, while the mechanisms of lncRNAs underlying osteosarcoma resistance to chemotherapy remain elusive. Here, LINC00520 was identified as a novel cisplatin resistance-related lncRNA in osteosarcoma, and its high expression was associated with poor prognosis of osteosarcoma patients. Functionally, LINC00520 could potentiate osteosarcoma resistance to cisplatin in vitro and in vivo. Mechanistically, LINC00520 bound to ENO1 and upregulated ENO1 protein expression by blocking FBXW7-mediated ENO1 ubiquitination and proteasomal degradation, thereby promoting glycolysis and ultimately inducing cisplatin resistance in osteosarcoma. Furthermore, METTL3 could stabilize and upregulate LINC00520 in an m6A-YTHDF2-dependent manner in osteosarcoma. This study proposes a novel lncRNA-driven mechanism for cisplatin resistance in osteosarcoma, and offers a promising therapeutic strategy for reversing chemoresistance in osteosarcoma by targeting the METTL3/LINC00520/ENO1/glycolysis axis. •LINC00520 potentiates osteosarcoma resistance to cisplatin in vitro and in vivo.•LINC00520 provokes glycolysis and cisplatin resistance through blocking FBXW7-mediated ENO1 ubiquitination in osteosarcoma.•METTL3 stabilizes and upregulates LINC00520 in an m6A-YTHDF2-dependent manner in osteosarcoma.•Targeting the METTL3/LINC00520/ENO1 axis is a promising therapeutic strategy for reversing chemoresistance in osteosarcoma.