RANBP2 Activates O-GlcNAcylation through Inducing CEBPα-Dependent OGA Downregulation to Promote Hepatocellular Carcinoma Malignant Phenotypes

摘要

Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and high mortality rate, with complex molecular alterations, including glycosylation. O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic modification process jointly controlled by the “writer” O-GlcNAc transferase (OGT) and “eraser” O-GlcNAcase (OGA), and an increase in total O-GlcNAc correlates with advanced malignant HCC phenotypes. The aim of our study was to explore the potential regulatory patterns underlying the OGT/OGA imbalance that contributes to HCC malignancies. We confirmed that RANBP2, one of the SUMO E3 ligases, downregulates OGA transcription while not affecting OGT. As a transcriptional factor positively regulating OGA, CEBPα was also SUMOylated and destabilized by RANBP2. Our in vitro and in vivo studies provide evidence of RANBP2 downregulating OGA and thus triggering O-GlcNAcylation in a CEBPα-dependent manner. The subsequent hyper-O-GlcNAcylation of protein substrates such as PGC1α via the RANBP2–CEBPα–OGA pathway may represent a pharmaceutical strategy for HCC treatment.