Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence
Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence
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Bclaf1 是 DNA 损伤诱导的衰老中重要的 NF-κB 信号转导器和 C/EBPβ 调节因子
DOI：
10.1038/cdd.2015.150
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发表时间：
2016-05-01
影响因子：
12.4
通讯作者：
Tang, J.
中科院分区：
文献类型：
--
作者：
Shao, A-w;Sun, H.;Tang, J.
诱导癌细胞衰老是抑制癌症生长的有效方法，并且它显著有助于治疗药物的功效。先前的研究表明，转录因子NF-κ B（活化B细胞的核因子κ-轻链增强子）和C/EBP β（CCAAT/增强子结合蛋白-β）通过上调促炎细胞因子，特别是白细胞介素-6（IL-6）和白细胞介素-8（IL-8），在衰老的建立中发挥关键作用。然而，目前尚不清楚这两个因素是如何激活响应衰老诱导的刺激，并随后调节基因转录。在这里，我们揭示了Bcl-2相关转录因子1（Bclaf 1）作为一种新的球员在治疗药物阿霉素诱导的衰老（TIS）在多种癌细胞。Bclaf 1在TIS期间通过ATM/Nemo/NF-κ B通路上调，并且是p65和c-Rel的直接靶点。NF-κ B对Bclaf 1的诱导对于TIS期间C/EBP β上调和IL-6/IL-8转录至关重要。Bclaf 1可以与C/EBP β的亮氨酸拉链区相互作用，并与C/EBP β协同上调IL-8。此外，我们表明，Bclaf 1是所需的阿霉素（Dox）治疗诱导的肿瘤抑制在异种移植肿瘤模型的有效性。这些发现表明，Bclaf 1在TIS期间将衰老诱导信号从NF-κ B B转导至C/EBP β中起关键作用，从而放大衰老建立的信号。鉴于最近的发现Bclaf 1参与肿瘤发生，我们的数据表明，Bclaf 1对NF-κ B的反应性可能决定治疗药物的有效性。
Inducing senescence in cancer cells is an effective approach to suppress cancer growth, and it contributes significantly to the efficacy of therapeutic drugs. Previous studies indicated that transcription factors NF-kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) and C/EBP beta (CCAAT/enhancer-binding protein-beta) play a critical role in the establishment of senescence by upregulating proinflammatory cytokines, notably interleukin-6 (IL-6) and interleukin-8 (IL-8). However, it is not clear how these two factors are activated in response to senescence-inducing stimuli and subsequently regulate gene transcription. Here, we reveal Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells. Bclaf1 is upregulated through the ATM/Nemo/NF-kappa B pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-kappa B is essential for C/EBP beta upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBP beta and cooperate with C/EBP beta to upregulate IL-8. Furthermore, we show that Bclaf1 is required for the effectiveness of doxorubicin (Dox) treatment-induced tumor suppression in a xenograft tumor model. These finding suggest that Bclaf1 plays a crucial role in transducing the senescence-inducing signal from NF-kappa B to C/EBP beta during TIS, thus amplifying the signals for the establishment of senescence. Given the recent revelation that Bclaf1 is involved in tumorigenesis, our data indicate that the responsiveness of Bclaf1 to NF-kappa B may determine the effectiveness of therapeutic drugs.