2. Academic Validation
  3. O-GlcNAcylation of DDX46 promotes hepatocellular carcinoma progression by activating the PI3K/Akt signaling pathway

O-GlcNAcylation of DDX46 promotes hepatocellular carcinoma progression by activating the PI3K/Akt signaling pathway

  • Biochim Biophys Acta Mol Cell Res. 2025 Oct 30;1873(1):120080. doi: 10.1016/j.bbamcr.2025.120080.
Qiujie Wang 1,  Yuanyuan Liu 1,  Kai Wang 1,  Ailong Huang 2,  Ni Tang 3,  Pai Peng 4
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology for Infectious 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 Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: ahuang@cqmu.edu.cn.
  • 3 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: nitang@cqmu.edu.cn.
  • 4 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: paipeng@cqmu.edu.cn.
PMID: 41176131 DOI: 10.1016/j.bbamcr.2025.120080
Abstract

O-linked-β-N-acetylglucosamine (O-GlcNAc) modification, also known as O-GlcNAcylation, is a dynamic and reversible protein modification. Aberrant O-GlcNAcylation are associated with the pathogenesis of cancers. DEAD-box helicase 46 (DDX46) is an ATP-dependent RNA helicase associated with Cancer development; however, its role and regulation in hepatocellular carcinoma (HCC) remain unclear. In this study, we observed that the level of O-GlcNAcylation of DDX46 was significantly elevated in HCC mouse models and patients. In addition, direct OGT-DDX46 interaction facilitates O-GlcNAcylation at the Ser257 site. Mechanically, we discovered that O-GlcNAcylation enhances the stability of DDX46 by impeding ubiquitin-mediated degradation. Increased expression of DDX46 activates the PI3K/Akt signaling pathway, promoting the proliferation and invasion of HCC. Taken together, our study highlights the critical role of DDX46 O-GlcNAcylation in HCC progression, thus proposing targeted disruption of this cascade as a novel therapeutic strategy for HCC treatment.

Keywords

DDX46; O-GlcNAcylation; PI3K/Akt; hepatocellular carcinoma; ubiquitination.

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