Inhibition of breast cancer progression by a novel histone deacetylase inhibitor, LW479, by down-regulating EGFR expression
Inhibition of breast cancer progression by a novel histone deacetylase inhibitor, LW479, by down-regulating EGFR expression
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新型组蛋白脱乙酰酶抑制剂 LW479 通过下调 EGFR 表达来抑制乳腺癌进展
DOI：
10.1111/bph.13165
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发表时间：
2015-08-01
影响因子：
7.3
通讯作者：
Yi, Zhengfang
中科院分区：
文献类型：
--
作者：
Li, Jingjie;Zhang, Tao;Yi, Zhengfang
背景和目的针对肿瘤表观遗传事件的化合物可能是抗癌治疗的重要补充。组蛋白脱乙酰酶抑制剂（HDACI）已成为一种有前途的新型癌症相关治疗干预措施，其中许多目前正在进行临床研究。在这里，我们评估了一种新型基于异羟肟酸盐的 HDACI（LW479）在乳腺癌进展中的作用，并探讨了其潜在机制。实验方法 LW479 使用 HDACI 筛查试剂盒进行鉴定。使用蛋白质印迹和流式细胞术分析LW479作为新型HDACI的生物学效应。在自发性和实验性乳腺癌小鼠模型中评估了 LW479 的作用。使用免疫共沉淀、免疫荧光染色和染色质免疫沉淀测定以及免疫组织化学分析来阐明 LW479 作用的分子基础。 主要结果 LW479 被鉴定为一种新型 HDACI，在一组乳腺癌细胞系中显示出显着的细胞毒性并诱导细胞凋亡以及细胞周期停滞。腹腔注射LW479显着抑制裸鼠乳腺肿瘤生长和肺转移。 LW479 还通过阻断转录因子 Sp1 和 HDAC1 与 EGFR 启动子区域的结合来降低 EGF 受体 (EGFR) 水平。 结论和意义我们的数据阐明了在 EGFR 表达异常的乳腺癌模型中 LW479 抑制肿瘤生长和转移的机制。 LW479可能是预防乳腺癌的候选药物。
Background and PurposeCompounds targeting epigenetic events of tumours are likely to be an important addition to anticancer therapy. Histone deacetylase inhibitors (HDACI) have emerged as a promising novel class for therapeutic interventions associated with cancer, and many of them are currently in clinical investigation. Here, we assessed a novel hydroxamate-based HDACI, LW479, in breast cancer progression and explored its underlying mechanism(s).Experimental ApproachLW479 was identified using the HDACI screening kit. Western blot and flow cytometry were used to analyse the biological effects of LW479 as a novel HDACI. The effects of LW479 were assessed in mouse models of spontaneous and experimental breast cancer. Co-immunoprecipitation, immunofluorescent staining and chromatin immunoprecipitation assays along with immunohistochemical analysis, were used to elucidate the molecular basis of the actions of LW479.Key ResultsLW479 was identified as a novel HDACI and showed marked cytotoxicity and induced apoptosis, as well as cell cycle arrest, in a panel of breast cancer cell lines. Intraperitoneal injections of LW479 markedly suppressed breast tumour growth and pulmonary metastasis in nude mice. LW479 also decreased levels of EGF receptors (EGFR) by blocking the binding of the transcription factor Sp1 and HDAC1 to the EGFR promoter region.Conclusions and ImplicationsOur data have elucidated the mechanisms underlying the inhibition by LW479 of tumour growth and metastasis, in models of breast cancer with aberrant EGFR expression. LW479 could be a candidate drug for breast cancer prevention.