Lv Yang, Lv Xiaotong, Zhang Jiahui, Cao Guozhen, Xu Changzhi, Zhang Buchang, Lin Wenchu
High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
University of Science and Technology of China, Hefei 230026, China.
Antioxidants (Basel). 2022 Mar 29;11(4):661. doi: 10.3390/antiox11040661.
Accumulating evidence has witnessed the Kelch-like ECH-associated protein 1(KEAP1)- nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis is the main regulatory factor of cell resistance to endogenous and exogenous oxidative assaults. However, there are few studies addressing the upstream regulatory factors of KEAP1. Herein, bioinformatic analysis suggests bromodomain-containing protein 4 (BRD4) as a potential top transcriptional regulator of KEAP1 in lung cancer. Using molecular and pharmacological approaches, we then discovered that BRD4 can directly bind to the promoter of to activate its transcription and down-regulate the stability of Nrf2 which in turn transcriptionally suppresses glucose-6-phosphate dehydrogenase (G6PD) in small cell lung cancer (SCLC), a highly proliferative and aggressive disease with limited treatment options. In addition, BRD4 could associate with the Nrf2 protein in a non-KEAP1-dependent manner to inhibit Nrf2 activity. Furthermore, simultaneous application of JQ1 and ATRA or RRx-001 yielded synergistic inhibition both in vitro and in vivo. These data suggest metabolic reprogramming by JQ1 treatment improves cell resistance to oxidative stress and might be a resistance mechanism to bromodomain and extra-terminal domain (BET) inhibition therapy. Altogether, our findings provide novel insight into the transcriptional regulatory network of BRD4 and KEAP1 and transcriptional regulation of the pentose phosphate pathway in SCLC.
越来越多的证据表明， Kelch样ECH相关蛋白1（KEAP1）-核因子（红系衍生2）样2（Nrf2）轴是细胞对内源性和外源性氧化攻击产生抗性的主要调节因子。然而，针对KEAP1上游调节因子的研究很少。在此，生物信息学分析表明含溴结构域蛋白4（BRD4）是肺癌中KEAP1潜在的顶级转录调节因子。然后，我们使用分子和药理学方法发现，BRD4可以直接结合到KEAP1的启动子上以激活其转录，并下调Nrf2的稳定性，这反过来又转录抑制小细胞肺癌（SCLC）中的葡萄糖-6-磷酸脱氢酶（G6PD），小细胞肺癌是一种增殖性高且侵袭性强、治疗选择有限的疾病。此外，BRD4可以以非KEAP1依赖的方式与Nrf2蛋白结合以抑制Nrf2活性。此外，同时应用JQ1和全反式维甲酸（ATRA）或RRx-001在体外和体内均产生协同抑制作用。这些数据表明，JQ1处理引起的代谢重编程可提高细胞对氧化应激的抗性，并且可能是对含溴结构域和额外末端结构域（BET）抑制疗法的一种抗性机制。总之，我们的研究结果为BRD4和KEAP1的转录调控网络以及小细胞肺癌中磷酸戊糖途径的转录调控提供了新的见解。
