AKAP1 enhances glycogen accumulation and hepatocarcinogenesis through YTHDF2-mediated G6PC mRNA decay.

During recent years, a growing body of evidence has revealed that metabolic rewiring of glycogen is a hallmark of cancer that plays a significant role in tumor development and progression. Nonetheless, the molecular mechanism underlying the dysregulation of glycogen remains largely unknown. In this study, using liver-specific AKAP1 depletion and overexpression mouse models, we demonstrated that AKAP1 deficiency markedly suppressed both chemical diethylnitrosamine/carbon tetrachloride (DEN/CCl₄)-induced and Akt/β-catenin oncogene-driven spontaneous hepatocellular carcinoma (HCC) by reducing hepatic glycogen content. Conversely, AKAP1 overexpression promoted glycogen accumulation and accelerated spontaneous hepatocarcinogenesis. Mechanically, m6A-dependent mRNA decay of glucose 6 phosphatase (G6PC) by YTHDF2, which was identified as a direct phosphorylation substrate at serine 289 and 359 sites by AKAP1 in a PKA-dependent manner, is important for AKAP1-caused glycogen accumulation and consequent hepatocarcinogenesis. Additionally, we found that AKAP1 expression is transcriptionally upregulated by Myc-associated zinc-finger protein (MAZ) in HCC cells. Importantly, treatment with AP-21, a competitive peptide inhibitor that disrupts mitochondrial localization of AKAP1, significantly reduced glycogen content and suppressed hepatocarcinogenesis without observable toxicity, highlighting its translational potential as a targeted therapeutic strategy for HCC. Collectively, our findings uncover a critical role for AKAP1 in driving HCC through metabolic reprogramming of glycogen, establishing AKAP1 as a promising therapeutic target for this malignancy.