2. Academic Validation
  3. O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma

O-GlcNAcylation of SPOP promotes carcinogenesis in hepatocellular carcinoma

  • Oncogene. 2023 Jan 5. doi: 10.1038/s41388-022-02589-z.
Peng Zhou # 1,  Wen-Yi Chang # 1,  De-Ao Gong # 1,  Lu-Yi Huang 1,  Rui Liu 1,  Yi Liu 1,  Jie Xia 1,  Kai Wang 2,  Ni Tang 3,  Ai-Long Huang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 2 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. wangkai@cqmu.edu.cn.
  • 3 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. nitang@cqmu.edu.cn.
  • 4 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. ahuang@cqmu.edu.cn.
  • # Contributed equally.
PMID: 36604567 DOI: 10.1038/s41388-022-02589-z
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.

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