Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression

Branched-chain amino acid (BCAA) catabolism is related to tumorigenesis. However, the underlying mechanism and specific contexts in which BCAAs affect tumor progression remain unclear. Here, we demonstrate that BCAA catabolism is activated in liver cancer cells without glutamine. Enhanced BCAA catabolism leads to BCAA-derived carbon and nitrogen flow toward nucleotide synthesis, stimulating cell-cycle progression and promoting cell survival. Mechanistically, O-GlcNAcylation increases under glutamine-deprivation conditions and stabilizes the PPM1K protein, leading to dephosphorylation of BCKDHA and enhanced decomposition of BCAAs. Dephosphorylation of BCKDHA and high expression of PPM1K promote tumorigenesis in vitro and in vivo and are closely related to the poor prognosis of clinical patients with hepatocellular carcinoma (HCC). Inhibition of BCAA and glutamine metabolism can further retard HCC growth in vivo. These results not only elucidate a mechanism by which BCAA catabolism affects tumorigenesis but also identify pBCKDHA and PPM1K as potential therapeutic targets and predictive biomarkers.

Automated summary

The catabolism of branched-chain amino acid (BCAA) is associated with tumorigenesis. This study reveals that BCAA catabolism is activated in liver cancer cells lacking glutamine. Enhanced BCAA catabolism leads to the production of BCAA-derived carbon and nitrogen for nucleotide synthesis, promoting cell-cycle progression and cell survival. The mechanism involves O-GlcNAcylation increasing under glutamine-deprivation conditions, stabilizing the PPM1K protein, and leading to dephosphorylation of BCKDHA and enhanced BCAA decomposition. Dephosphorylation of BCKDHA and high expression of PPM1K promote tumorigenesis and are associated with poor prognosis in hepatocellular carcinoma patients. Inhibiting BCAA and glutamine metabolism can slow down HCC growth in vivo. These findings shed light on the role of BCAA catabolism in tumorigenesis and identify pBCKDHA and PPM1K as potential targets for therapy and predictive biomarkers.