Researchers have uncovered a critical mechanism driving liver cancer progression through the acetylation of a key metabolic protein, providing potential new pathways for diagnosis and treatment of hepatocellular carcinoma (HCC).
The study, published in Protein & Cell, demonstrates how acetylation of the pyruvate dehydrogenase complex component X (PDHX) fundamentally alters cellular metabolism, promoting tumor growth. By disrupting the protein's normal function, cancer cells can redirect glucose metabolism towards aerobic glycolysis, a metabolic strategy that supports rapid cancer cell proliferation.
Specifically, researchers found that acetylation of PDHX at lysine 488 by the p300 acetyltransferase impedes the protein's interaction with other critical metabolic components. This modification reduces the pyruvate dehydrogenase complex's activity, effectively rerouting cellular energy production to support tumor development.
The research reveals significant clinical implications. PDHX acetylation was found to be upregulated in liver cancer tissues and correlated directly with poorer patient prognosis. By inhibiting this acetylation or restoring normal pyruvate dehydrogenase complex function, researchers demonstrated the potential to suppress tumor growth.
Particularly promising was the potential use of dichloroacetate (DCA), a PDH kinase inhibitor, which showed effectiveness in targeting glycolysis-dependent tumors with high PDHX acetylation levels. This suggests a potential therapeutic strategy for more personalized liver cancer treatments.
The study represents a substantial advancement in understanding cancer metabolism. By illuminating how post-translational modifications like acetylation can drive tumor progression, researchers have opened new avenues for diagnostic and therapeutic interventions. The identification of PDHX acetylation as both a potential biomarker and therapeutic target offers hope for more precise and effective liver cancer treatments.
Future research will likely focus on developing targeted inhibitors that can interrupt this metabolic transformation, potentially creating more effective interventions for patients with hepatocellular carcinoma.
