O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation

Zhongqi Feng, Jiaxin Yin, Zhirong Zhang, Zhen Chen, Luyi Huang*, Ni Tang*, Kai Wang* 

  细胞S期激酶相关蛋白2（SKP2，也称为p45）是一种重要的E3泛素连接酶，在细胞周期的调控中发挥关键功能。我们发现SKP2蛋白的34位丝氨酸发生O-GlcNAc糖基化修饰，O-GlcNAc修饰与泛素化修饰两种PTM之间的交互作用在调节肝细胞癌增殖中起着重要作用；为肝癌的治疗提供了潜在的新靶点。

Abstract

O-linked-β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC.

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DOI: https://doi.org/10.1038/s41388-024-02977-7

Full text: https://www.nature.com/articles/s41388-024-02977-7