2. Academic Validation
  3. ATF2 inhibits ani-tumor effects of BET inhibitor in a negative feedback manner by attenuating ferroptosis

ATF2 inhibits ani-tumor effects of BET inhibitor in a negative feedback manner by attenuating ferroptosis

  • Biochem Biophys Res Commun. 2021 Jun 18;558:216-223. doi: 10.1016/j.bbrc.2020.08.113.
Lina Wang 1,  Yibing Chen 2,  Yanjun Mi 3,  Jianghua Qiao 4,  Huan Jin 5,  Juntao Li 4,  Zhenduo Lu 4,  Qiming Wang 6,  Zhengzhi Zou 7
Affiliations

Affiliations

  • 1 Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital. Zhengzhou, 450008, China; MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 2 Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
  • 3 Department of Medical Oncology, Xiamen Cancer Hospital, First Affiliated Hospital of Xiamen University, Xiamen, 361003, China.
  • 4 Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital. Zhengzhou, 450008, China.
  • 5 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 6 Department of Clinical Oncology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China. Electronic address: qimingwang1006@126.com.
  • 7 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China. Electronic address: zouzhengzhi@m.scnu.edu.cn.
PMID: 33008584 DOI: 10.1016/j.bbrc.2020.08.113
Abstract

BET inhibitor (BETi) has potential therapeutic effects on human Cancer especially in breast Cancer. However, the detailed mechanisms remain unclear. Herein, we found that BETi JQ1 and I-BET-151 (I-BET) activated ATF2 through JNK1/2 pathway in breast Cancer cells MDA-MB-231 (MB-231). In addition, overexpression of ATF2 blocked the reduction of cell viability induced by JQ1 or I-BET in breast Cancer MB-231 and BT-549 cells, cervical Cancer HeLa cells and lung Cancer A549 cells. The induction of cell death by BETi was also attenuated by ATF2 in MB-231 and BT-549 cells. By contrast, depletion of ATF2 increased Cancer cell sensitivity to BETi. In MB-231 cells xenograft model, ATF2 significantly inhibited the anti-tumor effects of JQ1. By detection of the oxidized form gluthione, malondialdehyde and lipid ROS, we showed that overexpression of ATF2 inhibited Ferroptosis induced by BETi, whereas depletion of ATF2 promoted Ferroptosis by BETi. Furthermore, the underlying mechanisms of ATF2-reduced Ferroptosis were investigated. Overexpressed and depleted ATF2 were found to significantly upregulate and downregulate NRF2 protein and mRNA expression, respectively. The significantly positive correlations between NRF2 and ATF2 gene expression were found in breast, lung and cervical Cancer tissues from TCGA database. In NRF2-depleted MB-231 cells, ATF2 failed to attenuate JQ1-stimulated Ferroptosis. All these results suggested that ATF2 inhibited BETi-induced Ferroptosis by increasing NRF2 expression. Altogether, our findings illustrated ATF2 suppressed ani-tumor effects of BETi in a negative feedback manner by attenuating Ferroptosis. BETi combined with ATF2 or NRF2 inhibitor might be a novel strategy for treatment of human Cancer.

Keywords

ATF2; BET inhibitor; Cancer; Ferroptosis; NRF2.

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