ZMIZ1 Upregulation of TET3-Mediated Hydroxymethylation Induces M2 Polarization of Kupffer Cells in Hepatocellular Carcinogenesis by Mediating Notch1/c-Myc Signaling.

Hydroxymethylation of DNA, mediated by the ten-eleven translocation (TET) family of methylcytosine dioxygenases, represents a crucial epigenetic modification that manipulates gene expression in numerous biological processes. This study focuses on the effect of TET3 on the polarization of Kupffer cells (KCs) and its connection to the development of hepatocellular carcinoma (HCC). TET3 was found to be abundant in KCs, and its knockdown induced an M2-M1 phenotype shift, resulting in the suppression of viability, migration, and invasion of cocultured HCC cells. Additionally, the TET3 knockdown inhibited the tumorigenesis of HCC cells in nude mice. Downstream targets of TET3 were predicted using bioinformatics. TET3-mediated DNA hydroxymethylation of zinc finger MIZ-type containing 1 (ZMIZ1) promoter. The ZMIZ1 protein interacted with notch receptor 1 (Notch1) protein to activate the transcription of c-Myc. Silencing of ZMIZ1 in KCs similarly suppressed M2 polarization of KCs and malignant phenotype of cocultured HCC cells. However, these changes were counteracted by the overexpression of either Notch1 or c-Myc overexpression in KCs. In summary, this study demonstrates that TET3-mediated hydroxymethylation of ZMIZ1 enhances hepatocellular carcinogenesis by promoting M2 skewing of KCs through the Notch1/c-Myc axis.