Antioxidants stimulate BACH1-dependent tumor angiogenesis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Lung cancer progression is linked to angiogenesis, the formation of new blood vessels.
• Hypoxia-inducible factors (HIFs) typically regulate angiogenesis, but other factors are involved.
• The role of redox-sensitive transcription factors in tumor angiogenesis is increasingly recognized.

Purpose of the Study:

• To investigate the role of BTB and CNC homology 1 (BACH1) in controlling angiogenesis gene transcription in lung cancer.
• To determine if BACH1 acts independently of HIFs in regulating angiogenesis.
• To explore the therapeutic potential of targeting BACH1 and its associated pathways.

Main Methods:

• Assessed BACH1's control over angiogenesis genes in lung cancer cells, organoids, and xenografts.
• Administered antioxidants (vitamins C and E, N-acetylcysteine) under normoxia and hypoxia.
• Utilized BACH1-overexpressing and knockout cell models.
• Investigated BACH1 as a transcriptional target of HIF1α.
• Analyzed BACH1 expression in patient tumor samples.

Main Results:

• BACH1 regulates a wide array of angiogenesis genes.
• Antioxidants increased angiogenesis gene expression in a BACH1-dependent manner under normoxia.
• BACH1 levels are modulated by hypoxia and prolyl hydroxylase inhibitors.
• BACH1 is a HIF1α target, but its pro-angiogenic activity is HIF1α-independent.
• Increased BACH1 expression correlated with angiogenesis markers in patient tumors and sensitized tumors to anti-angiogenesis therapy.

Conclusions:

• BTB and CNC homology 1 (BACH1) is a critical oxygen- and redox-sensitive transcription factor for lung cancer angiogenesis.
• Targeting BACH1 or modulating redox balance presents a promising strategy for anti-angiogenesis therapy in lung cancer.