Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia.
Pigment Cell Melanoma Res. 2014 Nov;27(6):1126-37. doi: 10.1111/pcmr.12282. Epub 2014 Jul 3.
The transcription factor NF-kappaB (NF-kB) is a key regulator of cytokine and chemokine production in melanoma and is responsible for symptoms such as anorexia, fatigue, and weight loss. In addition, NF-kB is believed to contribute to progression of the disease by upregulation of cell cycle and anti-apoptotic genes and to contribute to resistance against targeted therapies and immunotherapy. In this study, we have examined the ability of the bromodomain and extra-terminal (BET) protein inhibitor I-BET151 to inhibit NF-kB in melanoma cells. We show that I-BET151 is a potent, selective inhibitor of a number of NF-kB target genes involved in induction of inflammation and cell cycle regulation and downregulates production of cytokines such as IL-6 and IL-8. SiRNA studies indicate that BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 caused transcriptional downregulation of the NF-kB subunit p105/p50. These results suggest that BET inhibitors may have an important role in treatment of melanoma where activation of NF-kB may have a key pathogenic role.
转录因子 NF-κB（NF-κB）是黑色素瘤中细胞因子和趋化因子产生的关键调节剂，负责引起厌食、疲劳和体重减轻等症状。此外，NF-κB 被认为通过上调细胞周期和抗凋亡基因促进疾病进展，并有助于对靶向治疗和免疫治疗的耐药性。在这项研究中，我们研究了溴结构域和末端（BET）蛋白抑制剂 I-BET151 抑制黑色素瘤细胞中 NF-κB 的能力。我们表明，I-BET151 是多种参与炎症诱导和细胞周期调节的 NF-κB 靶基因的有效、选择性抑制剂，并下调细胞因子（如 IL-6 和 IL-8）的产生。siRNA 研究表明，BRD2 是参与 NF-κB 调节的主要 BET 蛋白，I-BET151 导致 NF-κB 亚基 p105/p50 的转录下调。这些结果表明，BET 抑制剂在治疗黑色素瘤中可能具有重要作用，因为 NF-κB 的激活可能具有关键的发病作用。
