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ER|[alpha]| and ER|[beta]| expression and transcriptional activity are differentially regulated by HDAC inhibitors

机译:ER |α|和ER |β| HDAC抑制剂差异表达和转录活性

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The proliferative action of ER largely accounts for the carcinogenic activity of estrogens. By contrast, recent data show that ER displays tumor-suppressor properties, thus supporting the interest to identify compounds that could increase its activity. Here, we show that histone deacetylase inhibitors (HDI) upregulated ER protein levels, whereas it decreased ER expression. Part of this regulation took place at the mRNA level through a mechanism independent of de novo protein synthesis. In addition, we found that, in various cancer cells, the treatment with different HDI enhanced the ligand-dependent activity of ER more strongly than that of ER. On the other hand, in MDA-MB231 and HeLa cells, the expression of ERs modified the transcriptional response to HDI. The use of deletion mutants of both receptors demonstrated that AF1 domain of the receptors was required. Finally, we show that ER expression led to a dramatic increased in the antiproliferative activity of HDI, which correlated with a modification of the transcription of genes involved in cell cycle control by HDI. Altogether, these data demonstrate that the interference of ER and HDAC on the control of transcription and cell proliferation constitute a promising approach for cancer therapy.
机译:ER的增殖作用很大程度上解释了雌激素的致癌活性。相比之下,最近的数据表明ER表现出肿瘤抑制特性,从而支持了人们对鉴定可能增加其活性的化合物的兴趣。在这里,我们显示组蛋白脱乙酰基酶抑制剂(HDI)上调ER蛋白水平,而它降低ER表达。该调节的一部分通过独立于从头蛋白质合成的机制在mRNA水平发生。此外,我们发现,在各种癌细胞中,用不同的HDI处理比ER更能增强ER的配体依赖性活性。另一方面,在MDA-MB231和HeLa细胞中,ER的表达修饰了对HDI的转录反应。两个受体的缺失突变体的使用证明了受体的AF1结构域是必需的。最后,我们表明,ER表达导致HDI的抗增殖活性急剧增加,这与HDI参与细胞周期控制的基因的转录修饰有关。总而言之,这些数据表明ER和HDAC对转录和细胞增殖控制的干扰构成了用于癌症治疗的有前途的方法。

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