SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation.
SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation.
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DOI：
10.18632/oncotarget.15818
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发表时间：
2017-04-18
期刊：
影响因子：
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通讯作者：
Leopoldino AM
中科院分区：
文献类型：
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作者：
Almeida LO;Neto MPC;Sousa LO;Tannous MA;Curti C;Leopoldino AM
表观遗传修饰对于控制正常细胞过程和癌症发展至关重要。 DNA 甲基化和组蛋白乙酰化是涉及基因转录和驱动致癌过程的异常事件的主要表观遗传修饰。 SET 蛋白在许多癌症类型中积累，包括头颈鳞状细胞癌 (HNSCC)； SET 是 INHAT 复合体的成员，可抑制与组蛋白相关的基因转录并防止其乙酰化。我们探讨了 SET 蛋白积累如何影响基因表达的调节，重点关注 DNA 甲基化和组蛋白乙酰化。 24 种肿瘤抑制因子的 DNA 甲基化谱证明，SET 积累会降低 DNA 甲基化，并伴有 5-甲基胞苷的丢失、5-羟甲基胞嘧啶的形成以及 TET1 水平的增加，这表明存在活跃的 DNA 去甲基化机制。然而，一些抑制基因的表达在具有高SET水平的细胞中降低，这表明甲基化的丧失并不是调节基因表达的主要机制。 SET 积累还下调了 84 个转录因子中 32 个基因的表达，并且 SET 直接与下调基因启动子处的染色质相互作用，降低了组蛋白乙酰化。用 5-aza-2'-deoxycytidine (5-AZA) 和 Trichostatin A (TSA) 处理细胞后的基因表达分析表明，组蛋白乙酰化逆转了 SET 促进的转录抑制。这些结果表明 SET 在染色质动力学调节中具有新功能。此外，TSA 降低了 SET 蛋白水平和 SET 与基因启动子结合的能力，表明表观遗传修饰剂的施用可以有效逆转癌症中的 SET 表型。
Epigenetic modifications are essential in the control of normal cellular processes and cancer development. DNA methylation and histone acetylation are major epigenetic modifications involved in gene transcription and abnormal events driving the oncogenic process. SET protein accumulates in many cancer types, including head and neck squamous cell carcinoma (HNSCC); SET is a member of the INHAT complex that inhibits gene transcription associating with histones and preventing their acetylation. We explored how SET protein accumulation impacts on the regulation of gene expression, focusing on DNA methylation and histone acetylation. DNA methylation profile of 24 tumour suppressors evidenced that SET accumulation decreased DNA methylation in association with loss of 5-methylcytidine, formation of 5-hydroxymethylcytosine and increased TET1 levels, indicating an active DNA demethylation mechanism. However, the expression of some suppressor genes was lowered in cells with high SET levels, suggesting that loss of methylation is not the main mechanism modulating gene expression. SET accumulation also downregulated the expression of 32 genes of a panel of 84 transcription factors, and SET directly interacted with chromatin at the promoter of the downregulated genes, decreasing histone acetylation. Gene expression analysis after cell treatment with 5-aza-2′-deoxycytidine (5-AZA) and Trichostatin A (TSA) revealed that histone acetylation reversed transcription repression promoted by SET. These results suggest a new function for SET in the regulation of chromatin dynamics. In addition, TSA diminished both SET protein levels and SET capability to bind to gene promoter, suggesting that administration of epigenetic modifier agents could be efficient to reverse SET phenotype in cancer.