Tokumasu Miho, Sato Atsuko, Ito-Kureha Taku, Yamamoto Mizuki, Ohmine Nao, Semba Kentaro, Inoue Jun-Ichiro, Yamamoto Tadashi
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Cancer Gene Ther. 2025 May;32(5):573-583. doi: 10.1038/s41417-025-00897-6. Epub 2025 Apr 1.
NF-κB mediates transcriptional regulation crucial to many biological functions, and elevated NF-κB activity leads to autoimmune and inflammatory diseases, as well as cancer. Since highly aggressive breast cancers have few therapeutic molecular targets, clarification of key molecular mechanisms of NF-κB signaling would facilitate the development of more effective therapy. In this report, we show that Tob, a member of the Tob/BTG family of antiproliferative proteins, acts as a negative regulator of the NF-κB signal in breast cancer. Studies with 35 human breast cancer cell lines reveal that Tob expression is negatively correlated with NF-κB activity. Analysis of The Cancer Genome Atlas (TCGA) database of clinical samples reveals an inverse correlation between Tob expression and NF-κB activity. Tob knockdown in human breast cancer cells promoted overactivation of NF-κB upon TNF-α treatment, whereas overexpression of Tob inhibited TNF-α stimulation-dependent NF-κB activation. Mechanistically, Tob associates with the TNF receptor complex I and consequently inhibits RIPK1 polyubiquitylation, leading to possible prevention of overwhelming activation of NF-κB.
核因子-κB（NF-κB）介导对许多生物学功能至关重要的转录调控，而NF-κB活性升高会导致自身免疫性疾病、炎症性疾病以及癌症。由于侵袭性很强的乳腺癌几乎没有治疗性分子靶点，阐明NF-κB信号传导的关键分子机制将有助于开发更有效的治疗方法。在本报告中，我们表明抗增殖蛋白Tob/BTG家族的成员Tob在乳腺癌中作为NF-κB信号的负调节因子发挥作用。对35个人类乳腺癌细胞系的研究表明，Tob表达与NF-κB活性呈负相关。对临床样本的癌症基因组图谱（TCGA）数据库分析显示，Tob表达与NF-κB活性呈负相关。在人乳腺癌细胞中敲低Tob会促进TNF-α处理后NF-κB的过度激活，而Tob的过表达则抑制TNF-α刺激依赖性NF-κB激活。从机制上讲，Tob与TNF受体复合物I结合，从而抑制RIPK1多聚泛素化，可能导致预防NF-κB的过度激活。
