Histone acetylation activated-IGF2BP3 regulates cyclin D1 mRNA stability to drive cell cycle transition and tumor progression of hepatocellular carcinoma

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is an oncofetal protein, is strongly associated with tumor initiation and progression due to its upregulation. However, the regulatory mechanisms driving IGF2BP3 upregulation and its contribution to the development and progression in hepatocellular carcinoma (HCC) remain unclear. In this study, we demonstrated that IGF2BP3 is re-expressed in HCC mouse models, with elevated levels correlating with a poor prognosis in patients with HCC. Our data revealed that histone acetylation at the IGF2BP3 promoter region drives transcription activation of IGF2BP3 in primary hepatocytes. Notably, histone acetylation and transcriptional reactivation of IGF2BP3 were observed in human HCC tissues as well. Mechanistically, IGF2BP3 knockdown modulated the cell cycle and cell proliferation by limiting G1/S phase transition, which is dependent on cyclin D1. We further showed that IGF2BP3 maintains CCND1 mRNA stability by directly interacting with its 3 ' UTR. Importantly, IGF2BP3 recruits the RNA stabilizer PABPC1 to potentiate CCND1 mRNA stability. These two proteins synergistically protect CCND1 mRNA from degradation. Furthermore, IGF2BP3-depleted HCC cells were unable to form tumors in the xenograft model. High IGF2BP3 and CCND1 levels predicted poor outcomes in patients. Collectively, our findings highlight the pivotal role of the IGF2BP3/cyclin D1 axis and reveal a new regulatory mechanism for IGF2BP3 re-expression via transcriptional activation during hepatocarcinogenesis. These results indicate that the IGF2BP3/CCND1 axis is a promising prognostic biomarker and potential therapeutic target for HCC.