Epigenetic activation of JAG1 by AID contributes to metastasis of hepatocellular carcinoma

Metastasis is a major cause of fatality in hepatocellular carcinoma (HCC), although the precise mechanisms driving the metastatic process remain incompletely understood. In this study, we have made several important findings. Firstly, we have discovered that elevated activation-induced cytidine deaminase (AID) expression is positively correlated with Jagged 1 (JAG1) levels in clinically metastatic HCC patients. Moreover, we observed that depletion of either AID or JAG1 leads to a reduction in HCC metastasis. Secondly, we have identified AID acts as a transcriptional regulator that regulates JAG1 transcription by interacting with histone acetyltransferase 1 (HAT1) in metastatic HCC cells. Furthermore, our results demonstrate that any domains of AID can cooperate with HAT1 to enhance JAG1 transcription. Importantly, we have determined that the AID/HAT1 complex directly binds to specific regions within the JAG1 gene body, specifically -1.504 kb to -1.104 kb region, thereby influencing the epigenetic state of the JAG1 promoter through modulating histone methylation, histone acetylation, and DNA methylation. Furthermore, we have elucidated that the AID-JAG1/NOTCH-c-FOS axis plays a pivotal role in facilitating HCC metastasis. Consequently, the inhibitory effects of MG149 on both AID and JAG1 significantly mitigate the progression of HCC. This investigation uncovers a heretofore unappreciated function of AID as a transcriptional regulator in the metastasis of HCC, heralding a promising therapeutic approach.