Regulation of the high basal expression of the manganese superoxide dismutase gene in aggressive breast cancer cells
Regulation of the high basal expression of the manganese superoxide dismutase gene in aggressive breast cancer cells
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DOI：
10.1016/j.freeradbiomed.2011.03.013
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发表时间：
2011-06-15
影响因子：
7.4
通讯作者：
Becuwe, Philippe
中科院分区：
文献类型：
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作者：
Ennen, Marie;Minig, Vanessa;Becuwe, Philippe
据报道，锰超氧化物歧化酶（MnSOD）的高基础表达在侵袭性乳腺癌细胞中，根据未知的机制，并有助于其侵袭能力。在这里，我们报告的参与Sp1和核因子-κ B（NF-κ B）转录因子在这种高基础表达MnSOD在侵袭性乳腺癌细胞。Sp1的抑制或失活表明，它通过染色质免疫沉淀（ChIP）测定和MnSOD近端启动子的功能分析鉴定的独特结合位点在侵袭性乳腺癌细胞中的高MnSOD表达中起着至关重要的作用。用特异性NF-κ B抑制剂肽处理细胞显著降低了高基础MnSOD表达。ChIP检测显示组成型p50/p65 NF-κ B复合物与MnSOD内含子增强子元件结合，与H3组蛋白的超乙酰化相关。最后，MnSOD的高基础表达导致侵袭性乳腺癌细胞中缺乏受损DNA结合2（DDB 2）蛋白的表达。DDB 2过表达阻止了Sp1和NF-κ B与MnSOD基因上各自元件的结合。这些结果有助于更好地理解MnSOD的上调，这可能是临床上重要的乳腺肿瘤进展的预测。(C)2011 Elsevier Inc. All rights reserved.
A high basal expression of manganese superoxide dismutase (MnSOD) has been reported in aggressive breast cancer cells, according to an unknown mechanism, and contributes to their invasive abilities. Here, we report the involvement of Sp1 and nuclear factor-kappa B (NF-kappa B) transcription factors in this high basal expression of MnSOD in aggressive breast cancer cells. Suppression or inactivation of Sp1 showed that it plays an essential role in the high MnSOD expression in aggressive breast cancer cells through a unique binding site identified by chromatin immunoprecipitation (ChIP) assay and functional analysis of the MnSOD proximal promoter. Treatment of cells with a specific NF-kappa B inhibitor peptide decreased significantly high basal MnSOD expression. A ChIP assay showed binding of a constitutive p50/p65 NF-kappa B complex to the MnSOD intronic enhancer element, associated with hyperacetylation of the H3 histone. Finally, high basal expression of MnSOD resulted in the lack of expression of Damaged DNA binding 2 (DDB2) protein in aggressive breast cancer cells. DDB2 overexpression prevented the binding of Sp1 as well as of NF-kappa B to their respective elements on the MnSOD gene. These results contribute to a better understanding of MnSOD up-regulation, which may be clinically important in the prediction of breast tumor progression. (C) 2011 Elsevier Inc. All rights reserved.