N4BP3 promotes angiogenesis in hepatocellular carcinoma by binding with KAT2B

• DOI: 10.1111/cas.15498
• Publication Date: 2022-07-18T13:27:59Z
• Authors: Hexu Han; Wei Zhu; Ting Lin; Cuixia Liu; Hengyong Zhai
• Keywords: STAT3 Transcription Factor; 0301 basic medicine; 0303 health sciences; Carcinoma, Hepatocellular; Neovascularization, Pathologic; Liver Neoplasms; Mice, Nude; Original Articles; Lysine Acetyltransferases; Sorafenib; 3. Good health; Histones; Oxygen; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Angiogenesis Inducing Agents; Cell Proliferation

AbstractAlthough angiogenesis is a critical event in hepatocellular carcinoma (HCC), and this process provides the tumor with sufficient oxygen and nutrients, the precise molecular mechanism by which it occurs is not fully understood. NEDD4 binding protein 3 (N4BP3) was identified in this study as a novel pro‐angiogenic factor in HCC cell lines and tissues. We discovered that N4BP3 was significantly expressed in HCC and that its level of expression was positively correlated with the density of tumor microvessels in HCC tissues. Cell biology experiments have shown that N4BP3 knockdown in HCC cells significantly inhibits the formation of complete tubular structures by HUVECs in vitro and HCC angiogenesis in vivo. In HCC cells, overexpression of N4BP3 has the opposite effects. Further cell and molecular biology experiments have revealed that N4BP3 interacts with KAT2B (lysine acetyltransferase 2B), increasing signal transducer and activator of transcription 3 (STAT3) expression by regulating the distribution of acetyl‐histone H3 (Lys27) (H3K27ac) in its promoter region. This, in addition, regulates the activity of the STAT3 signaling pathway, which promotes the proliferation of microvessels in HCC and accelerates the malignant process of the tumor. In vivo experiments in nude mice have confirmed our findings, and also suggested that N4BP3 could be a potential target for the treatment of HCC in combination with sorafenib.