EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells.
EZH2 mediates lidamycin-induced cellular senescence through regulating p21 expression in human colon cancer cells.
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EZH2 通过调节人结肠癌细胞中 p21 的表达来介导力达霉素诱导的细胞衰老。
DOI：
10.1038/cddis.2016.383
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发表时间：
2016-11-24
影响因子：
9
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Sha MQ;Zhao XL;Li L;Li LH;Li Y;Dong TG;Niu WX;Jia LJ;Shao RG;Zhen YS;Wang Z
利达霉素（Lidamycin， LDM）是国内新发现的具有较强抗肿瘤活性的烯二炔类抗生素。然而，目前尚不清楚LDM是否具有潜在的影响其抗肿瘤活性的分子靶点。zeste同源物2增强子（Enhancer of zeste homolog 2, EZH2）作为组蛋白赖氨酸甲基转移酶，介导组蛋白3赖氨酸27 （H3K27me3）的三甲基化。高EZH2水平与肿瘤的侵袭性、转移及不良预后呈正相关。在这里，我们的目的是研究EZH2在LDM诱导的人类结肠癌细胞衰老中的作用，以及LDM的细胞毒性。通过衰老相关的β-半乳糖苷酶染色、细胞周期阻滞和衰老调节因子p21在HCT116和SW620细胞中的分子变化，我们发现LDM对EZH2高水平结肠癌细胞的抑制作用相对更强，并在ic50剂量范围内诱导不可逆的细胞衰老。更重要的是，研究发现LDM在诱导p21和细胞衰老时，在蛋白和mRNA水平上显著抑制EZH2的表达。与其他组蛋白赖氨酸甲基转移酶相比，LDM也选择性地抑制EZH2的表达。用sirna敲低p21可消除ldm诱导的衰老，而敲低EZH2可显著增加p21的表达并导致衰老表型。LDM降低了p21启动子区域EZH2和H3K27me3水平的富集。此外，EZH2过表达可减少LDM暴露后的细胞衰老、p21表达和DNA损伤反应。LDM在异种移植动物模型中也显示出强大的抗肿瘤功效。总的来说，我们的工作首次证明了EZH2可能通过调节p21表达和DNA损伤效应来介导LDM诱导衰老的作用，至少部分介导LDM诱导衰老的作用。因此，EZH2可能作为一种潜在的靶点和生物标志物来指示强效enediyne抗肿瘤药物的临床疗效。
Lidamycin (LDM) is a novel member of the enediyne antibiotics identified in China with potent antitumor activity. However, it remains unclear whether LDM has potential molecular targets that may affect its antitumor activity. Enhancer of zeste homolog 2 (EZH2) functions as a histone lysine methyltransferase and mediates trimethylation on histone 3 lysine 27 (H3K27me3). High EZH2 level is found to be positively correlated with the aggressiveness, metastasis and poor prognosis of cancer. Here, we aim to study the role of EZH2 in LDM-induced senescence, as well as in the cytotoxicity of LDM in human colon cancer cells. LDM is found to be relatively more potent in inhibiting the colon cancer cells harboring high EZH2 level and induces irreversible cellular senescence at IC 50 dose range, as evidenced by senescence-associated β-galactosidase staining, cell cycle arrest and molecular changes of senescence regulators including p21 in HCT116 and SW620 cells. More importantly, LDM is found to markedly inhibit EZH2 expression at both protein and mRNA levels upon the induction of p21 and cellular senescence. LDM also selectively inhibits EZH2 expression as compared with other histone lysine methyltransferases. Knockdown of p21 with siRNAs abolishes LDM-induced senescence, whereas EZH2 knockdown markedly increases p21 expression and causes senescent phenotype. Enrichment of both EZH2 and H3K27me3 levels in the p21 promoter region is reduced by LDM. Moreover, EZH2 overexpression reduces cellular senescence, p21 expression and DNA damage response upon LDM exposure. LDM also demonstrates potent antitumor efficacy in xenografted animal models. Collectively, our work provides first demonstration that EZH2 may mediate, at least partially, the senescence-inducing effects of LDM by regulating p21 expression and DNA damage effect. Thus, EZH2 may serve as a potential target and biomarker to indicate the clinical efficacy of the potent enediyne antitumor drug.