BACH1 stabilization by antioxidants facilitates hepatocellular carcinoma metastasis.

Reactive oxygen species (ROS) plays certain contradictory and complex roles in the carcinogenesis and progression of cancers. In such process, antioxidants enable to promote the malignant invasion and migration of hepatocellular carcinoma (HCC) cells, but the underlying mechanisms remain elusive. Here, we found that two antioxidants, glutathione (GSH) and N-acetylcysteine (NAC), stabilized BACH1 (i.e., BTB and CNC homology 1) by decreasing ROS levels, thus facilitated BACH1-dependent migration of HCC cells in vitro and their metastasis in vivo. Mechanistically, knockout of BACH1 mildly alleviated endoplasmic reticulum stress/adaptive unfolded protein response (UPR) and repressed epithelial-mesenchymal transition (EMT) to inhibit cell migration. Further examinations revealed that BACH1 binds to consensus ARE sites in the promoter regions of key genes responsible for glycolytic pathway to activate their transcription, while concurrently repressing the expression of mitochondrial respiratory chain genes. This dual regulation thereby promoted the Warburg effect and facilitated HCC cell migration driven by glycolysis. The BACH1-regulated metabolic reprogramming was further unraveled by non-targeted metabolomics. Collectively, these demonstrate that the redox-sensitive transcription factor BACH1 functions as a crucial metastasis-promoter of HCC, and thus antioxidants stimulate BACH1-dependent HCC metastasis.