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Pharmacological inhibition of EZH2 by ZLD1039 suppresses tumor growth and pulmonary metastasis in melanoma cells in vitro and in vivo

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机构： [1]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 [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China [3]Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China

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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.Copyright © 2023 Elsevier Inc. All rights reserved.

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基金编号： grant number 2021YFH0145] and the Excellent Youth Fund of Sichuan Cancer Hospital [grant number YB2021024

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出版当年[2023]版：

大类 | 2 区医学

小类 | 2 区药学

最新[2023]版：

大类 | 2 区医学

小类 | 2 区药学

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出版当年[2023]版：

Q1 PHARMACOLOGY & PHARMACY

最新[2023]版：

Q1 PHARMACOLOGY & PHARMACY

影响因子： 5.3 最新[2023版] 5.2 最新五年平均 5.3 出版当年[2023版] 5.2 出版当年五年平均 5.8 出版前一年[2022版]

第一作者：

第一作者机构： [1]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 [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China

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通讯作者：

通讯机构： [*1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, 17#3rd Section, Ren Min South Road, Chengdu 610041, China.

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