BACH1 promotes hepatocellular carcinoma progression by targeting PDP1 towards the PI3K-AKT-mTOR signaling activation

Hepatocellular carcinoma (HCC) remains a major threat to public health owing to its high incidence and mortality rates. While the pro-tumor role of BACH1 (i.e., BTB and CNC homology 1) in HCC has been previously reported, the present study uncovers a novel mechanism by which BACH1 regulates tumor progression. Through CCK-8, colony formation, and flow cytometry assays, we confirmed that BACH1 promoted the proliferation, colony formation and cell cycle progression of HCC cells, but inhibited its apoptosis. Following BACH1 knockout, the mitochondrial membrane potential was decreased, intracellular levels of reactive oxygen species (ROS) were increased, cell apoptosis was significantly enhanced, and the growth of xenograft tumors in mice was suppressed. In terms of mechanistic investigation, luciferase reporter gene assays demonstrated that BACH1 directly bound to the antioxidant response element (ARE) sites in the promoter region of the pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) gene. This binding activated the transcriptional expression of PDP1, thereby promoting cellular energy metabolism. Concurrently, western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses revealed, for the first time, that BACH1 activated the TGFB1/SMAD signaling pathway related to cell growth, synergistically promoting tumor cell proliferation. Furthermore, PDP1 was identified as an oncogenic factor, reduced expression of PDP1 suppressed the colony formation and tumorigenesis of HCC cells. Downregulation of either BACH1 or PDP1 suppressed the PI3K-AKT-mTOR signaling pathway, and a PI3K activator effectively reversed the inhibition of HCC cell proliferation induced by BACH1 or PDP1 downregulation. Collectively, our present study reveals a novel regulatory axis of BACH1-PDP1-PI3K-AKT-mTOR, thereby providing potential intervention targets and a theoretical basis for the molecular precision therapy of HCC.