Background: Mucosal melanoma (MM) is epidemiologically, biologically, and molecularly distinct from cutaneous melanoma. Current treatment strategies have failed to significantly improve the prognosis for MM patients. This study aims to identify therapeutic targets and develop combination strategies by investigating the mechanisms underlying the tumorigenesis and progression of MM. Methods: We analyzed the copy number amplification of enhancer of zeste homolog 2 (EZH2) in 547 melanoma patients and investigated its correlation with clinical prognosis. Utilizing cell lines, organoids, and patient-derived xenograft models, we assessed the impact ofEZH2on cell proliferation and sensitivity to ferroptosis. Further, we explored the mechanisms of ferroptosis resistance associated withEZH2by conducting RNA sequencing and chromatin immunoprecipitation sequencing. Results:EZH2copy number amplification was closely associated with malignant phenotype and poor prognosis in MM patients.EZH2was essential for MM cell proliferation in vitro and in vivo. Moreover, genetic perturbation ofEZH2rendered MM cells sensitized to ferroptosis. Combination treatment ofEZH2inhibitor with ferroptosis inducer significantly inhibited the growth of MM. Mechanistically,EZH2inhibited the expression of Krüpple-Like factor 14 (KLF14), which binds to the promoter of solute carrier family 7 member 11 (SLC7A11) to repress its transcription. Loss ofEZH2therefore reduced the expression ofSLC7A11, leading to reduced intracellularSLC7A11-dependent glutathione synthesis to promote ferroptosis. Conclusion: Our findings not only establishEZH2as a biomarker for MM prognosis but also highlight theEZH2-KLF14-SLC7A11axis as a potential target for MM treatment.
背景：黏膜黑色素瘤在流行病学、生物学及分子特征上均与皮肤黑色素瘤存在显著差异。当前的治疗策略未能显著改善黏膜黑色素瘤患者的预后。本研究旨在通过探究黏膜黑色素瘤发生与进展的分子机制，寻找潜在治疗靶点并开发联合治疗策略。方法：我们分析了547例黑色素瘤患者中zeste同源物2增强子（EZH2）的拷贝数扩增情况，并探讨其与临床预后的相关性。利用细胞系、类器官及患者来源的异种移植模型，评估了EZH2对细胞增殖及铁死亡敏感性的影响。进一步通过RNA测序和染色质免疫沉淀测序，探究了EZH2介导的铁死亡抵抗机制。结果：EZH2拷贝数扩增与黏膜黑色素瘤的恶性表型及不良预后密切相关。EZH2在体外和体内均为黏膜黑色素瘤细胞增殖所必需。此外，EZH2的基因扰动可增强黏膜黑色素瘤细胞对铁死亡的敏感性。EZH2抑制剂与铁死亡诱导剂的联合治疗显著抑制了黏膜黑色素瘤的生长。机制上，EZH2通过抑制Krüpple样因子14（KLF14）的表达发挥作用，而KLF14可与溶质载体家族7成员11（SLC7A11）的启动子结合并抑制其转录。EZH2缺失导致SLC7A11表达下调，进而减少细胞内依赖SLC7A11的谷胱甘肽合成，最终促进铁死亡发生。结论：本研究不仅确立了EZH2作为黏膜黑色素瘤预后的生物标志物，同时揭示了EZH2-KLF14-SLC7A11轴可作为黏膜黑色素瘤治疗的潜在靶点。
肿瘤(癌症)患者之家