Aldolase A accelerates hepatocarcinogenesis by refactoring c-Jun transcription

TL;DR

Aldolase A promotes liver cancer by altering c-Jun activity, and its removal slows cancer growth in mice and cells.

Contribution

Aldolase A's nuclear role in enhancing c-Jun transcription through phosphorylation is newly identified in hepatocarcinogenesis.

Findings

ALDOA knockout reduces HCC proliferation in vitro and in vivo.

ALDOA interacts with c-Jun to increase its Thr93 phosphorylation and transcriptional activity.

Y364 mutation in ALDOA disrupts c-Jun interaction and fails to rescue cell proliferation.

Abstract

Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of Aldoa strikingly decreased HCC development in vivo. Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.

Image 1

•ALDOA knockout significantly inhibits HCC cell proliferation without affecting normal liver cells.•ALDOA knockout partially limits the glycolytic flux in HCC cells.•ALDOA interacts with c-Jun and regulates its transcriptional activity by affecting c-Jun (Thr93) phosphorylation in HCC cells.•ALDOA binds to c-Jun to enhance the transcription of the ALDOA gene.•AAV8-mediated liver Aldoa knockdown in the HCC mouse model decreases HCC development.

ALDOA knockout significantly inhibits HCC cell proliferation without affecting normal liver cells.

ALDOA knockout partially limits the glycolytic flux in HCC cells.

ALDOA interacts with c-Jun and regulates its transcriptional activity by affecting c-Jun (Thr93) phosphorylation in HCC cells.

ALDOA binds to c-Jun to enhance the transcription of the ALDOA gene.

AAV8-mediated liver Aldoa knockdown in the HCC mouse model decreases HCC development.

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