Antioxidants stimulate BACH1-dependent tumor angiogenesis

• Published in: The Journal of clinical investigation Vol. 133; no. 20; pp. 1 - 12
• Main Authors: Wang, Ting, Dong, Yongqiang, Huang, Zhiqiang, Zhang, Guoqing, Zhao, Ying, Yao, Haidong, Hu, Jianjiang, Tüksammel, Elin, Cai, Huan, Liang, Ning, Xu, Xiufeng, Yang, Xijie, Schmidt, Sarah, Qiao, Xi, Schlisio, Susanne, Strömblad, Staffan, Qian, Hong, Jiang, Changtao, Treuter, Eckardt, Bergo, Martin O.
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 16.10.2023
• Subjects: Acetylcysteine; Angiogenesis; Antioxidants; Biomedical research; Cancer therapies; Gene expression; Genomes; Homology; Hypoxia; Lung cancer; Medicin och hälsovetenskap; Metastasis; Organoids; Prolyl hydroxylase; Protein expression; Proteins; Transcription factors; Tumors; Vitamins
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI169671

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 BACHT-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACHT-overexpressing cells and decreased in BACHT-knockout cells in the absence of antioxidants. BACHT levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both H/FTA-knockout and WT cells. BACHT was found to be a transcriptional target of HIFTa, but BACHT's ability to stimulate angiogenesis gene expression was HIFTa independent. Antioxidants increased tumor vascularity in vivo in a BACHT-dependent fashion, and overexpressing BACHT rendered tumors sensitive to antiangiogenesis therapy. BACHT expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACHT is an oxygen- and redox-sensitive angiogenesis transcription factor.