Interleukin-8 Expression Is Regulated by Histone Deacetylases through the Nuclear Factor-κB Pathway in Breast Cancer
Interleukin-8 Expression Is Regulated by Histone Deacetylases through the Nuclear Factor-κB Pathway in Breast Cancer
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DOI：
10.1124/mol.108.047332
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发表时间：
2008-11-01
影响因子：
3.6
通讯作者：
Lazennec, Gwendal
中科院分区：
文献类型：
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作者：
Chavey, Carine;Muehlbauer, Marcus;Lazennec, Gwendal
我们最近报道了趋化因子白细胞介素8（IL-8）/CXCL 8在侵袭性雌激素受体（ER α）阴性乳腺癌细胞中过表达，与ER α阳性乳腺癌细胞相比。我们现在证明，组蛋白脱乙酰酶（HDAC）在ER α阳性MCF-7乳腺癌细胞中IL-8基因表达的调节中起着重要作用。用HDAC抑制剂曲马斯他汀A（TSA）处理MCF-7细胞导致MCF-7细胞中IL-8蛋白和RNA水平的强烈上调。MCF-7细胞中IL-8的表达呈时间和浓度依赖性。此外，连续和转染实验表明，HDAC抑制剂诱导的IL-8是转录的，主要涉及IL-8启动子的核因子-κ B（NF-κ B）位点。这些观察结果通过TSA存在下MCF-7细胞中NF-κ B活性的上调得到证实。此外，通过腺病毒递送显性阴性I κ B或I κ B激酶复合物2（IKK 2）突变体阻断NF-κ B途径，可消除组蛋白去乙酰化酶抑制剂对IL-8基因的诱导作用。HDAC抑制剂触发IKK磷酸化并上调p65核转位，尽管它们降低了I κ B α的蛋白水平，这是NF-κ B激活的原因。TSA增加乙酰化组蛋白3与IL-8基因启动子的结合。总之，我们的研究结果表明HDAC对NF-κ B通路的抑制是ER α阳性乳腺癌细胞中IL-8低表达的原因。
We have reported recently that the chemokine interleukin 8 (IL-8)/CXCL8 was overexpressed in invasive estrogen receptor (ER alpha)-negative breast cancer cells compared with ER alpha-positive breast cancer cells. We now demonstrate that histone deacetylases (HDACs) play an essential role in the regulation of IL-8 gene expression in ER alpha-positive MCF-7 breast cancer cells. Treatment of MCF-7 cells with the HDAC inhibitor trichostatin A (TSA) led to a strong up-regulation of IL-8 protein and RNA levels in MCF-7 cells. The up-regulation of IL-8 in MCF-7 cells was time- and concentration-dependent. Moreover, run-on and transfection experiments demonstrated that IL-8 induction by HDAC inhibitors was transcriptional and involved mainly the nuclear factor-kappa B (NF-kappa B) site of the IL-8 promoter. These observations are corroborated by an up-regulation of NF-kappa B activity in MCF-7 cells in the presence of TSA. In addition, blocking NF-kappa B pathway by adenoviral delivery of a dominant-negative I kappa B or I kappa B kinase complex 2 (IKK2) mutant abolished IL-8 gene induction by histone deacetylase inhibitors. HDAC inhibitors triggered IKK phosphorylation and up-regulated p65 nuclear translocation, although they decreased the protein levels of I kappa B alpha, which accounts for NF-kappa B activation. TSA increased binding of acetylated histone 3 to the IL-8 gene promoter. In summary, our results demonstrate that NF-kappa B pathway repression by HDAC is responsible for the low expression of IL-8 in ER alpha-positive breast cancer cells.