Zhu Yongxia, Zhang Lidan, Song Xuejiao, Zhang Qiangsheng, Wang Ting, Xiao Hongtao, Yu Luoting
Department of Clinical Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China.
Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Biochem Pharmacol. 2023 Apr;210:115493. doi: 10.1016/j.bcp.2023.115493. Epub 2023 Mar 8.
The incidence and mortality rate of malignant melanoma are increasing worldwide. Metastasis reduces the efficacy of current melanoma therapies and leads to poor prognosis for patients. EZH2 is a methyltransferase that promotes the proliferation, metastasis, and drug resistance of tumor cells by regulating transcriptional activity. EZH2 inhibitors could be effective in melanoma therapies. Herein, we aimed to investigate whether the pharmacological inhibition of EZH2 by ZLD1039, a potent and selective S-adenosyl-l-methionine-EZH2 inhibitor, suppresses tumor growth and pulmonary metastasis in melanoma cells. Results showed that ZLD1039 selectively reduced H3K27 methylation in melanoma cells by inhibiting EZH2 methyltransferase activity. Additionally, ZLD1039 exerted excellent antiproliferative effects on melanoma cells in 2D and 3D culture systems. Administration of ZLD1039 (100 mg/kg) by oral gavage caused antitumor effects in the A375 subcutaneous xenograft mouse model. RNA sequencing and GSEA revealed that the ZLD1039-treated tumors exhibited changes in the gene sets enriched from the "Cell Cycle" and "Oxidative Phosphorylation", whereas the "ECM receptor interaction" gene set had a negative enrichment score. Mechanistically, ZLD1039 induced G0/G1 phase arrest by upregulating p16 and p27 and inhibiting the functions of the cyclin D1/CDK6 and cyclin E/CDK2 complexes. Moreover, ZLD1039 induced apoptosis in melanoma cells via the mitochondrial reactive oxygen species apoptotic pathway, consistent with the changes in transcriptional signatures. ZLD1039 also exhibited excellent antimetastatic effects on melanoma cells in vitro and in vivo. Our data highlight that ZLD1039 may be effective against melanoma growth and pulmonary metastasis and thus could serve as a therapeutic agent for melanoma.
全球范围内，恶性黑色素瘤的发病率和死亡率都在上升。转移会降低当前黑色素瘤治疗的疗效，并导致患者预后不良。EZH2是一种甲基转移酶，可通过调节转录活性促进肿瘤细胞的增殖、转移和耐药性。EZH2抑制剂可能对黑色素瘤治疗有效。在此，我们旨在研究强效选择性S-腺苷-L-甲硫氨酸-EZH2抑制剂ZLD1039对EZH2的药理学抑制是否能抑制黑色素瘤细胞的肿瘤生长和肺转移。结果表明，ZLD1039通过抑制EZH2甲基转移酶活性选择性降低黑色素瘤细胞中的H3K27甲基化。此外，ZLD1039在二维和三维培养系统中对黑色素瘤细胞具有出色的抗增殖作用。通过口服灌胃给予ZLD1039（100mg/kg）在A375皮下异种移植小鼠模型中产生了抗肿瘤作用。RNA测序和基因集富集分析（GSEA）显示，经ZLD1039处理的肿瘤在“细胞周期”和“氧化磷酸化”富集的基因集中表现出变化，而“细胞外基质受体相互作用”基因集的富集分数为负。从机制上讲，ZLD1039通过上调p16和p27并抑制细胞周期蛋白D1/细胞周期蛋白依赖性激酶6（CDK6）和细胞周期蛋白E/细胞周期蛋白依赖性激酶2（CDK2）复合物的功能诱导G0/G1期阻滞。此外，ZLD1039通过线粒体活性氧凋亡途径诱导黑色素瘤细胞凋亡，这与转录特征的变化一致。ZLD1039在体外和体内对黑色素瘤细胞也表现出出色的抗转移作用。我们的数据表明，ZLD1039可能对黑色素瘤生长和肺转移有效，因此可作为黑色素瘤的治疗药物。
