Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Cancer Res. 2022 Dec 16;82(24):4555-4570. doi: 10.1158/0008-5472.CAN-22-0959.
Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression.
The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells.
肿瘤异质性是黑色素瘤的一个关键特征，它阻碍了有效治疗方法的发展。为了克服这一障碍，我们发现 LINC00518（LENOX；长非编码 RNA 增强氧化磷酸化）是一种在所有已知黑色素瘤细胞状态中表达的黑色素瘤特异性 lncRNA，对体外和体内黑色素瘤的存活至关重要。从机制上讲，LENOX 促进了 RAP2C GTP 酶与线粒体分裂调节剂 DRP1 的结合，增加了 DRP1 S637 的磷酸化、线粒体融合和氧化磷酸化。在用 MAPK 抑制剂治疗后，LENOX 的表达上调，促进了从糖酵解到氧化磷酸化的代谢转换，并赋予了对 MAPK 抑制的抗性。因此，LENOX 和 RAP2C 的联合沉默与 MAPK 抑制剂协同作用，根除黑色素瘤细胞。因此，黑色素瘤依赖于 lncRNA LENOX，它在黑色素瘤发生和进展过程中作用于优化线粒体功能。
lncRNA LENOX 是一种新型的黑色素瘤代谢调节剂，可与 MAPK 抑制剂联合靶向，以根除黑色素瘤细胞。
