AP-21 peptide inhibitor reduces glycogen accumulation and suppresses hepatocarcinogenesis in mouse models

Metabolic rewiring of glycogen is a recognized hallmark of cancer, playing a significant role in tumor development and progression, yet its precise molecular mechanisms in hepatocellular carcinoma (HCC) remain largely unknown. Current standard-of-care treatments for HCC often face challenges with efficacy and side effects, highlighting the need for novel therapeutic targets. This study investigates AKAP1, a scaffolding protein, and its role in dysregulating glycogen metabolism, which could offer a new avenue for HCC intervention.

Researchers utilized liver-specific AKAP1 depletion and overexpression mouse models to study its impact on HCC. They induced HCC using both chemical diethylnitrosamine/carbon tetrachloride (DEN/CCl₄) and oncogene-driven Akt/β-catenin spontaneous models. The primary endpoint was the assessment of hepatic glycogen content and tumor progression. Mechanistic studies involved identifying phosphorylation sites and analyzing m6A-dependent mRNA decay. Importantly, a competitive peptide inhibitor, AP-21, was administered to disrupt mitochondrial localization of AKAP1, and its effects on glycogen and HCC were evaluated.

AKAP1 deficiency markedly suppressed both chemical and oncogene-driven HCC by reducing hepatic glycogen content. Conversely, AKAP1 overexpression promoted glycogen accumulation and accelerated spontaneous hepatocarcinogenesis. Mechanistically, AKAP1 was identified as directly phosphorylating YTHDF2 at serine 289 and 359 sites in a PKA-dependent manner. This phosphorylation is crucial for m6A-dependent mRNA decay of glucose 6 phosphatase (G6PC), which in turn drives AKAP1-caused glycogen accumulation and subsequent hepatocarcinogenesis. Additionally, Myc-associated zinc-finger protein (MAZ) was found to transcriptionally upregulate AKAP1 expression in HCC cells. The most compelling finding for translational potential was:

Treatment with AP-21, a competitive peptide inhibitor, significantly reduced glycogen content and suppressed hepatocarcinogenesis without observable toxicity in mouse models, highlighting its therapeutic promise.