BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma

Area of Science:

• Oncology
• Metabolic pathways
• Cancer biology

Background:

• Hypoxia is prevalent in solid tumors like hepatocellular carcinoma (HCC), driving tumor cell survival.
• Hypoxia-inducible factors (HIFs), especially HIF-1α, are key mediators of metabolic adaptation in hypoxic environments.
• Branched-chain amino transferase 1 (BCAT1) plays a role in amino acid metabolism, involving α-ketoglutarate (α-KG).

Purpose of the Study:

• To elucidate the mechanism by which BCAT1 influences HIF-1α stability and promotes HCC survival.
• To investigate the role of BCAT1 in α-KG consumption and its impact on hypoxia-related pathways.
• To evaluate the therapeutic potential of BCAT1 inhibition in HCC models.

Main Methods:

• Investigated BCAT1's role in consuming α-KG and stabilizing HIF-1α.
• Assessed the impact of BCAT1 inhibition on α-KG-dependent enzymes and HIF-1α.
• Evaluated a BCAT1 inhibitor (ERG245) in vivo, alone and with tyrosine kinase inhibitors (TKIs).
• Validated BCAT1 and HIF-1α target gene expression in HCC clinical samples.

Main Results:

• BCAT1 was found to consume α-KG, leading to HIF-1α stabilization.
• This stabilization suppressed α-KG-dependent oxygen dehydrogenase and prolyl hydroxylase-domain protein (PHD).
• BCAT1 inhibition demonstrated therapeutic potential in preclinical HCC models.
• Over-expression of BCAT1 and HIF-1α downstream genes was confirmed in HCC samples.

Conclusions:

• BCAT1 promotes HCC growth and survival by facilitating HIF-1α-mediated metabolic reprogramming.
• Targeting BCAT1 represents a viable therapeutic strategy for hepatocellular carcinoma.
• The interplay between BCAT1, α-KG, and HIF-1α is a critical vulnerability in HCC.