BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer
文献类型：期刊论文
| 作者 | Lv, Yang2,3,4; Lv, Xiaotong2,3,4; Zhang, Jiahui2,3,4; Cao, Guozhen2,3,4; Xu, Changzhi1; Zhang, Buchang1; Lin, Wenchu2,4 |
| 刊名 | ANTIOXIDANTS
 |
| 出版日期 | 2022-04-01 |
| 卷号 | 11 |
| 关键词 | small cell lung cancer BRD4 KEAP1 Nrf2 pentose phosphate pathway |
| DOI | 10.3390/antiox11040661 |
| 通讯作者 | Lin, Wenchu(wenchu@hmfl.ac.cn) |
| 英文摘要 | 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 KEAP1 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. |
| WOS关键词 | BET INHIBITOR RESISTANCE ; ACTIVATION ; THERAPY ; PATHWAY |
| 资助项目 | National Natural Science Foundation of China[81972191] ; National Natural Science Foundation of China[81672647] ; Science and Technology Major Project of Anhui Province[18030801140] ; 100-Talent Program of the Chinese Academy of Sciences ; High Magnetic Field Laboratory of Anhui Province |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Food Science & Technology |
| 语种 | 英语 |
| 出版者 | MDPI |
| WOS记录号 | WOS:000786224700001 |
| 资助机构 | National Natural Science Foundation of China ; Science and Technology Major Project of Anhui Province ; 100-Talent Program of the Chinese Academy of Sciences ; High Magnetic Field Laboratory of Anhui Province |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/128591]  |
| 专题 | 中国科学院合肥物质科学研究院 |
| 通讯作者 | Lin, Wenchu |
| 作者单位 | 1.Anhui Univ, Inst Phys Sci, Hefei 230601, Peoples R China 2.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China 3.Univ Sci & Technol China, Hefei 230026, Peoples R China 4.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Hefei 230031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lv, Yang,Lv, Xiaotong,Zhang, Jiahui,et al. BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer[J]. ANTIOXIDANTS,2022,11. |
| APA | Lv, Yang.,Lv, Xiaotong.,Zhang, Jiahui.,Cao, Guozhen.,Xu, Changzhi.,...&Lin, Wenchu.(2022).BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.ANTIOXIDANTS,11. |
| MLA | Lv, Yang,et al."BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer".ANTIOXIDANTS 11(2022). |
入库方式： OAI收割
来源：合肥物质科学研究院
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