METTL3介导的LINC00520的m6A修饰通过抑制ENO1的泛素化赋予骨肉瘤糖酵解能力和化学抗性。

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

作者信息

Wei Xianfu, Feng Jinyan, Chen Long, Zhang Chao, Liu Yongheng, Zhang Yan, Xu Yao, Zhang Jin, Wang Jinwu, Yang Houzhi, Han Xiuxin, Wang Guowen

机构信息

Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China; State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, National Clinical Research Center for Cancer, Tianjin, 300060, PR China; Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, PR China.

出版信息

Cancer Lett. 2024 Aug 19:217194. doi: 10.1016/j.canlet.2024.217194.

DOI:10.1016/j.canlet.2024.217194

PMID:39168299

Abstract

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.

摘要

化疗耐药仍然是限制骨肉瘤治疗的主要障碍，严重影响骨肉瘤青少年患者的预后。最近，有报道称长链非编码RNA（lncRNA）参与了化疗耐药，而lncRNA在骨肉瘤化疗耐药中的潜在机制仍不清楚。在此，LINC00520被鉴定为骨肉瘤中一种新的顺铂耐药相关lncRNA，其高表达与骨肉瘤患者的不良预后相关。在功能上，LINC00520在体外和体内均可增强骨肉瘤对顺铂的耐药性。机制上，LINC00520与ENO1结合，通过阻断FBXW7介导的ENO1泛素化和蛋白酶体降解来上调ENO1蛋白表达，从而促进糖酵解并最终诱导骨肉瘤对顺铂的耐药性。此外，METTL3可以在骨肉瘤中以m6A-YTHDF2依赖的方式稳定并上调LINC00520。本研究提出了一种新的lncRNA驱动的骨肉瘤顺铂耐药机制，并提供了一种有前景的治疗策略，即通过靶向METTL3/LINC00520/ENO1/糖酵解轴来逆转骨肉瘤的化疗耐药性。