Antioxidants stimulate BACH1-dependent tumor angiogenesis
Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcri...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI169671 |
| _version_ | 1797634432060882944 |
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| author | Ting Wang Yongqiang Dong Zhiqiang Huang Guoqing Zhang Ying Zhao Haidong Yao Jianjiang Hu Elin Tüksammel Huan Cai Ning Liang Xiufeng Xu Xijie Yang Sarah Schmidt Xi Qiao Susanne Schlisio Staffan Strömblad Hong Qian Changtao Jiang Eckardt Treuter Martin O. Bergo |
| author_facet | Ting Wang Yongqiang Dong Zhiqiang Huang Guoqing Zhang Ying Zhao Haidong Yao Jianjiang Hu Elin Tüksammel Huan Cai Ning Liang Xiufeng Xu Xijie Yang Sarah Schmidt Xi Qiao Susanne Schlisio Staffan Strömblad Hong Qian Changtao Jiang Eckardt Treuter Martin O. Bergo |
| author_sort | Ting Wang |
| collection | DOAJ |
| description | Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1–overexpressing cells and decreased in BACH1-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1α, but BACH1’s ability to stimulate angiogenesis gene expression was HIF1α independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor. |
| first_indexed | 2024-03-11T12:07:39Z |
| format | Article |
| id | doaj.art-5f0458f746fd4c7c9b584178a0c221af |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:39Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-5f0458f746fd4c7c9b584178a0c221af2023-11-07T16:20:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-10-0113320Antioxidants stimulate BACH1-dependent tumor angiogenesisTing WangYongqiang DongZhiqiang HuangGuoqing ZhangYing ZhaoHaidong YaoJianjiang HuElin TüksammelHuan CaiNing LiangXiufeng XuXijie YangSarah SchmidtXi QiaoSusanne SchlisioStaffan StrömbladHong QianChangtao JiangEckardt TreuterMartin O. BergoLung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1–overexpressing cells and decreased in BACH1-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1α, but BACH1’s ability to stimulate angiogenesis gene expression was HIF1α independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor.https://doi.org/10.1172/JCI169671Angiogenesis |
| spellingShingle | Ting Wang Yongqiang Dong Zhiqiang Huang Guoqing Zhang Ying Zhao Haidong Yao Jianjiang Hu Elin Tüksammel Huan Cai Ning Liang Xiufeng Xu Xijie Yang Sarah Schmidt Xi Qiao Susanne Schlisio Staffan Strömblad Hong Qian Changtao Jiang Eckardt Treuter Martin O. Bergo Antioxidants stimulate BACH1-dependent tumor angiogenesis The Journal of Clinical Investigation Angiogenesis |
| title | Antioxidants stimulate BACH1-dependent tumor angiogenesis |
| title_full | Antioxidants stimulate BACH1-dependent tumor angiogenesis |
| title_fullStr | Antioxidants stimulate BACH1-dependent tumor angiogenesis |
| title_full_unstemmed | Antioxidants stimulate BACH1-dependent tumor angiogenesis |
| title_short | Antioxidants stimulate BACH1-dependent tumor angiogenesis |
| title_sort | antioxidants stimulate bach1 dependent tumor angiogenesis |
| topic | Angiogenesis |
| url | https://doi.org/10.1172/JCI169671 |
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