SUMOylation of E2F1 Regulates Expression of EZH2.
SUMOylation of E2F1 Regulates Expression of EZH2.
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DOI：
10.1158/0008-5472.can-20-1259
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发表时间：
2020-10-01
期刊：
影响因子：
11.2
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Du L;Fakih MG;Rosen ST;Chen Y
EZH 2（polycomb repressive complex 2（PRC 2）的酶亚基）的表达升高通常发生在癌症中。EZH 2表达导致基因沉默，所述基因通过组蛋白H3在所述基因启动子的赖氨酸27处的三甲基化（H3 K27 me 3）来抑制肿瘤形成和转移。然而，EZH 2酶活性的抑制剂在临床试验中没有显示出预期的抗癌功效，这表明需要其他策略来解决EZH 2过表达。在这里，我们表明SUMO化，一种翻译后修饰，其特征在于小泛素样修饰物（SUMO）蛋白共价连接到靶蛋白上的赖氨酸（Lys）残基，增强EZH 2转录。敲低SUMO激活酶SAE 2或药理学抑制SUMO化导致EZH 2 mRNA和蛋白水平降低以及H3 K27 me 3水平降低。SUMO化通过增强E2 F1转录激活因子与EZH 2启动子的结合来调节EZH 2表达。抑制SUMO化不仅导致EZH 2 mRNA和蛋白水平降低，而且还增加了EZH 2沉默的基因的表达，例如抑制上皮-间质转化和转移的E-钙粘蛋白。在超过6，500份不同癌症类型的患者肿瘤样本中，UBA 2和EZH 2的表达呈正相关。总之，我们的研究结果表明，抑制SUMO化可能是解决EZH 2过表达和改善当前癌症治疗方法的潜在策略。
Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at said gene promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here we show that SUMOylation, a post-translational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacological inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 were positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches.