O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma
Peng Zhou(周鹏), Wen-yi Chang（常文译）, De-ao Gong（龚德敖）, Lu-yi Huang, Rui Liu, Yi Liu, Jie Xia, Kai Wang*, Ni Tang* & Ai-long Huang*
Abstract
Aberrantly elevated O-GlcNAcylation level is commonly observed in human cancer patients, and has been proposed as a potential therapeutic target. Speckle-type POZ protein (SPOP), an important substrate adaptor of cullin3-RING ubiquitin ligase, plays a key role in the initiation and development of various cancers. However, the regulatory mechanisms governing SPOP and its function during hepatocellular carcinoma (HCC) progression remain unclear. Here, we show that, in HCC, SPOP is highly O-GlcNAcylated by O-GlcNAc transferase (OGT) at Ser96. In normal liver cells, the SPOP protein mainly localizes in the cytoplasm and mediates the ubiquitination of the oncoprotein neurite outgrowth inhibitor-B (Nogo-B) (also known as reticulon 4 B) by recognizing its N-terminal SPOP-binding consensus (SBC) motifs. However, O-GlcNAcylation of SPOP at Ser96 increases the nuclear positioning of SPOP in hepatoma cells, alleviating the ubiquitination of the Nogo-B protein, thereby promoting HCC progression in vitro and in vivo. In addition, ablation of O-GlcNAcylation by an S96A mutation increased the cytoplasmic localization of SPOP, thereby inhibiting the Nogo-B/c-FLIP cascade and HCC progression. Our findings reveal a novel post-translational modification of SPOP and identify a novel SPOP substrate, Nogo-B, in HCC. Intervention with the hyper O-GlcNAcylation of SPOP may provide a novel strategy for HCC treatment.
These authors contributed equally: Peng Zhou(周鹏), Wen-yi Chang（常文译）, De-ao Gong（龚德敖）.
Full text: https://www.nature.com/articles/s41388-022-02589-z
O-GlcNAc糖基化修饰SPOP促进肝细胞癌发生发展
正常肝细胞中，斑点型锌指结构蛋白 SPOP定位于细胞质，其底物Nogo-B发生泛素化，无法激活下游c-FLIP蛋白；
肝癌细胞中，E3泛素连接酶SPOP发生氧连接N-乙酰葡萄糖胺修饰后入核，导致Nogo-B/c-FLIP信号轴激活。
Cite this article: Zhou, P., Chang, Wy., Gong, Da. et al. O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma. Oncogene (2023). https://doi.org/10.1038/s41388-022-02589-z
