Aldolase A accelerates hepatocarcinogenesis by refactoring c-Jun transcription

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) exhibits significant reprogramming of glucose metabolism, with abundant glycolytic enzymes.
• Aldolase A (ALDOA) is a key glycolytic enzyme, but its specific role in HCC development remains largely unexplored.

Purpose of the Study:

• To investigate the role of ALDOA in HCC proliferation and elucidate its underlying molecular mechanisms.

Main Methods:

• Utilized ALDOA knockout and overexpression models in vitro and in vivo.
• Assessed glycolytic flux, nuclear translocation of ALDOA, and interaction with c-Jun.
• Analyzed c-Jun phosphorylation at Thr93 mediated by P21-activated protein kinase.
• Correlated ALDOA expression with c-Jun phosphorylation and patient prognosis.
• Examined ALDOA's role in diethylnitrosamine-induced HCC models.

Main Results:

• ALDOA knockout suppressed HCC proliferation, while overexpression promoted it.
• ALDOA knockout partially limited glycolytic flux and reduced c-Jun Thr93 phosphorylation.
• ALDOA directly interacted with c-Jun in the nucleus, facilitating its phosphorylation and transcriptional activity.
• A specific mutation (Y364) in ALDOA disrupted its interaction with c-Jun.
• Elevated ALDOA expression correlated with phosphorylated c-Jun (Thr93) and poor prognosis in HCC patients.
• ALDOA was upregulated during HCC progression in animal models, and its knockdown inhibited HCC development.

Conclusions:

• ALDOA is a critical driver of HCC development and proliferation.
• ALDOA activates c-Jun-mediated oncogene transcription, contributing to HCC pathogenesis.
• Targeting ALDOA presents a promising therapeutic strategy for hepatocellular carcinoma.