Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression
Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression
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靶向 BRD4 蛋白通过下调 eIF4E 表达来抑制 NSCLC 的生长。
DOI：
10.1080/15384047.2018.1423923
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发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
Wang, Xuerong
中科院分区：
文献类型：
--
作者：
Gao, Zhongyuan;Yuan, Ting;Wang, Xuerong
肺癌是全球癌症相关死亡的主要原因。溴结构域和末端外结构域（BET）蛋白充当基因转录调控的表观基因组阅读器。在BET家族成员中，BRD 4被充分研究，但其在非小细胞肺癌中的机制尚未阐明。eIF 4 E调节基因翻译，已被证明在肺癌的进展中起重要作用。在这项研究中，我们首先证实BET抑制剂JQ 1和I-BET 151抑制NSCLC的生长，同时下调eIF 4 E表达。然后我们发现使用siRNA敲低BRD 4表达抑制NSCLC的生长以及降低eIF 4 E蛋白水平。此外，eIF 4 E的过表达部分废除了JQ 1的生长抑制作用，而eIF 4 E的敲除增强了JQ 1的抑制作用。此外，JQ 1处理或敲低BRD 4表达降低eIF 4 E mRNA水平，并通过荧光素酶报告基因测定抑制其启动子活性。JQ 1处理显著降低eIF 4 E启动子与BRD 4的结合。最后，在异种移植小鼠模型中，JQ 1抑制H460肿瘤的生长，同时下调eIF 4 E mRNA和蛋白水平。这些发现表明，通过JQ 1、I-BET 151或BRD 4沉默抑制BET通过降低eIF 4 E转录以及随后的mRNA和蛋白质表达来抑制非小细胞肺癌的生长。考虑到BET在表观遗传学上调节基因转录，我们的研究结果不仅揭示了BET调节eIF 4 E在肺癌中的新机制，而且还指出了通过共靶向eIF 4 E来增强BET靶向癌症治疗的新策略。
Lung cancer is the leading cause of cancer-related death worldwide. Bromodomain and extraterminal domain (BET) proteins act as epigenome readers for gene transcriptional regulation. Among BET family members, BRD4 was well studied, but for its mechanism in non-small cell lung carcinoma has not been elucidated. eIF4E regulates gene translation and has been proved to play an important role in the progression of lung cancer. In this study, we first confirmed that BET inhibitors JQ1 and I-BET151 suppressed the growth of NSCLCs, in parallel with downregulated eIF4E expression. Then we found that knockdown of BRD4 expression using siRNAs inhibited the growth of NSCLCs as well as decreased eIF4E protein levels. Moreover, overexpression of eIF4E partially abrogated the growth inhibitory effect of JQ1, while knockdown of eIF4E enhanced the inhibitory effect of JQ1. Furthermore, JQ1 treatment or knockdown of BRD4 expression decreased eIF4E mRNA levels and inhibited its promoter activity by luciferase reporter assay. JQ1 treatment significantly decreased the binding of eIF4E promoter with BRD4. Finally, JQ1 inhibited the growth of H460 tumors in parallel with downregulated eIF4E mRNA and protein levels in a xenograft mouse model. These findings suggest that inhibition of BET by JQ1, I-BET151, or BRD4 silencing suppresses the growth of non-small cell lung carcinoma through decreasing eIF4E transcription and subsequent mRNA and protein expression. Considering that BET regulates gene transcription epigenetically, our findings not only reveal a new mechanism of BET-regulated eIF4E in lung cancer, but also indicate a novel strategy by co-targeting eIF4E for enhancing BET-targeted cancer therapy.