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O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma
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 va...
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Published in: | Oncogene 2023-03, Vol.42 (10), p.725-736 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/s41388-022-02589-z |