Dipartimento di Morfologia Umana e Scienze Biomediche Città Studi, University of Milan, Milan, Italy.
Mol Cancer Res. 2009 Aug;7(8):1328-41. doi: 10.1158/1541-7786.MCR-08-0548. Epub 2009 Aug 11.
Here, we show that NF-kappaB-HIF-1 interaction contributed to breast cancer metastatic capacity by means of an incomplete epithelial/mesenchymal transition and influencing migration, as shown in 1833 (human) and 4T1 (mouse) metastatic cells after different stimuli. The 1833 and the transforming growth factor-beta1-exposed 4T1 cells showed both epithelial (E-cadherins) and mesenchymal (N-cadherins and vimentin) markers, and common mechanisms contributed to the retention of certain epithelial characteristics and the control of migration. The complex NF-kappaB-HIF-1 reciprocal regulation and the enhanced c-Jun expression played a functional role in exacerbating the invasiveness of 1833 cells after p50/p65 transfection and of 4T1 cells exposed to transforming growth factor-beta1. Twist expression seemed to exert a permissive role also regulating epithelial/mesenchymal transition markers. After c-Src wild-type (Srcwt) transfection, c-Src-signal transducer overexpression in 1833 cells increased HIF-1 transactivating activity and invasiveness, and changed E-cadherin/N-cadherin ratio versus mesenchymal phenotype. The transcription factor pattern and the motile phenotype of metastatic 1833 cells were influenced by p65-lysine acetylation and HDAC-dependent epigenetic mechanisms, which positively regulated basal NF-kappaB and HIF-1 activities. However, HDAC3 acted as a corepressor of NF-kappaB activity in parental MDA-MB231 cells, thus explaining many differences from the derived 1833 clone, including reduced HIF-1alpha and c-Jun expression. Invasiveness was differently affected by HDAC knockdown in 1833 and MDA-MB231 cells. We suggest that acetylation/deacetylation are critical in establishing the bone-metastatic gene signature of 1833 cells by regulating the activity of NF-kappaB and HIF-1, and further clarify the epigenetic control of transcription factor network in the motile phenotype of 1833 cells.
在这里，我们通过不完全的上皮/间充质转化和迁移影响来展示 NF-κB-HIF-1 相互作用有助于乳腺癌转移能力，这在经过不同刺激后的 1833（人）和 4T1（鼠）转移性细胞中得到了证明。暴露于 NF-κB 抑制剂的 1833 细胞和转化生长因子-β1 暴露的 4T1 细胞均显示出上皮（E-钙粘蛋白）和间充质（N-钙粘蛋白和波形蛋白）标志物，并且共同的机制有助于保留某些上皮特征和控制迁移。NF-κB-HIF-1 相互作用的复杂调节和 c-Jun 表达的增强在增强 p50/p65 转染后 1833 细胞的侵袭性和转化生长因子-β1 暴露的 4T1 细胞的侵袭性方面发挥了功能作用。Twist 表达似乎也发挥了允许作用，调节上皮/间充质转化标志物。在 c-Src 野生型（Srcwt）转染后，c-Src 信号转导物在 1833 细胞中的过度表达增加了 HIF-1 反式激活活性和侵袭性，并改变了 E-钙粘蛋白/N-钙粘蛋白比值与间充质表型。转移性 1833 细胞的转录因子模式和运动表型受 p65-赖氨酸乙酰化和 HDAC 依赖性表观遗传机制的影响，这些机制正向调节基础 NF-κB 和 HIF-1 活性。然而，HDAC3 在亲本 MDA-MB231 细胞中作为 NF-κB 活性的核心抑制剂发挥作用，从而解释了许多与衍生的 1833 克隆之间的差异，包括 HIF-1alpha 和 c-Jun 表达减少。在 1833 和 MDA-MB231 细胞中，HDAC 敲低对侵袭性的影响不同。我们建议乙酰化/去乙酰化通过调节 NF-κB 和 HIF-1 的活性，在建立 1833 细胞的骨转移基因特征方面至关重要，并进一步阐明转录因子网络在 1833 细胞运动表型中的表观遗传控制。
