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

2021; Multidisciplinary Digital Publishing Institute; Volume: 13; Issue: 14 Linguagem: Inglês

10.3390/cancers13143475

2072-6694

Xiaoming Liu, Xingyu Chen, Mengqing Xiao, Yuxing Zhu, Renjie Gong, Jianye Liu, Qinghai Zeng, Canxia Xu, Xiong Chen, Fen Wang, Ke Cao,

Galectins and Cancer Biology

O-GlcNAcylation is an important post-translational modification (PTM) jointly controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Aberrant hyper-O-GlcNAcylation is reported to yield hepatocellular carcinoma (HCC) malignancy, but the underlying mechanisms of the OGT/OGA imbalance responsible for HCC tumorigenesis remain largely unknown. Here, we report that RAN-binding protein 2 (RANBP2), one of the small ubiquitin-like modifier (SUMO) E3 ligases, contributed to malignant phenotypes in HCC. RANBP2 was found to facilitate CCAAT/enhancer-binding protein alpha (CEBPα) SUMOylation and degradation by direct interplay with CEBPα. As a transcriptional factor, CEBPα was verified to augment OGA transcription, and further experiments demonstrated that RANBP2 enhanced the O-GlcNAc level by downregulating OGA transcription while not affecting OGT expression. Importantly, we provided in vitro and in vivo evidence of HCC malignant phenotypes that RANBP2 triggered through an imbalance of OGT/OGA and subsequent higher O-GlcNAcylation events for oncogenic proteins such as peroxisome proliferative-activated receptor gamma coactivator 1 alpha (PGC1α) in a CEBPα-dependent manner. Altogether, our results show a novel molecular mechanism whereby RANBP2 regulates its function through CEBPα-dependent OGA downregulation to induce a global change in the hyper-O-GlcNAcylation of genes, such as PGC1α, encouraging the further study of promising implications for HCC therapy.