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bioRxiv · 10.1101/2025.03.18.643938

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

Bu, Q.·Zhang, Y.
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Abstract

Hepatocellular carcinoma (HCC) is remaining to be accepted as a major challenge against public health, because of its high incidence and mortality. Herein, we explored underlying molecular mechanisms by which BTB and CNC homology 1 (BACH1) facilitated progression of HCC. Functional experiments indicated that BACH1 promoted the proliferation, clonogenicity, cycle progression of HCC cells, and inhibited apoptosis. Knockout of BACH1 decreased mitochondrial membrane potential, augmented reactive oxygen species (ROS) generation, induced cell apoptosis, and reduced malignant growth of xenograft neoplasms in mice. Mechanistic experiments revealed that BACH1 bound to the ARE sites in the promoter region of pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1), so to activate its transcriptional expression and promote cellular energy metabolism. Interestingly, BACH1 enables activation of the cell growth-related TGF-{beta}1/SMAD signaling pathway, which further promoted the malignant proliferation of HCC cells. Of note, PDP1 functions as a tumor promoter, since lowering its expression levels suppressed the clonogenicity in HCC cells. Furthermore, such downregulation in BACH1 or PDP1 could inhibit the PI3K-AKT-mTOR signaling. In conclusion, these reveal that BACH1 manifests a dominant tumor-promoting factor and is hence viewed as a promising therapeutic target of HCC, because it promotes HCC progression by targeting PDP1 towards PI3K-AKT-mTOR pathway activation.

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Bu, Q., Zhang, Y.. 2025-03-19. BACH1 promotes hepatocellular carcinoma progression by targeting PDP1 towards the PI3K-AKT-mTOR signaling activation. https://doi.org/10.1101/2025.03.18.643938

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