Antioxidants stimulate BACH1-dependent tumor angiogenesis

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

doi:10.1172/JCI169671

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Wang, T. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Dong, Y. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Huang, Z. in: JCI | PubMed | Google Scholar |

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Zhang, G. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Zhao, Y. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Yao, H. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Hu, J. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Tüksammel, E. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Cai, H. in: JCI | PubMed | Google Scholar |

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Liang, N. in: JCI | PubMed | Google Scholar |

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Xu, X. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Yang, X. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Schmidt, S. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Qiao, X. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Schlisio, S. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Strömblad, S. in: JCI | PubMed | Google Scholar |

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Qian, H. in: JCI | PubMed | Google Scholar |

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Jiang, C. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Treuter, E. in: JCI | PubMed | Google Scholar

¹Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

²Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

³Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

⁴Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

⁵Department of Medicine, Karolinska Institutet, Stockholm, Sweden

⁶Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

⁷Department of Physiology and Pathophysiology, Peking University, Beijing, China

Find articles by Bergo, M. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI169671.
Copyright © 2023, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published August 31, 2023 - Version history

Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs); but growing evidence indicate 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 reactive oxygen species levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following vitamin C and E and N-acetylcysteine administration in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1–overexpressing cells and decreased in BACH1-knockouts in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1a-knockout and wild-type cells. BACH1 was found to be a transcriptional target of HIF1α but BACH1’s ability to stimulate angiogenesis gene expression was HIF1a independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to anti-angiogenesis therapy. BACH1 expression in tumor sections from lung cancer patients correlates with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor.

Version 1 (August 31, 2023): In-Press Preview

Antioxidants stimulate BACH1-dependent tumor angiogenesis

Article tools

Metrics

Go to

Antioxidants stimulate BACH1-dependent tumor angiogenesis

Article tools

Metrics

Go to

Sign up for email alerts