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Peer-reviewedCC BY 4.0Advanced Science

SUMOylated DDX3 Promotes HBV Replication and Tumor Growth of Hepatocellular Carcinoma via TRIM28‐DDX3‐KLF4α Signaling Axis

  • Yanfang Yang1,2
  • Ting Kong1
  • Binghan Wang3
  • Xiaoli Jin1
  • Lan Huang1
  • Nan Zhang1,4
  • Siyu Tang5,6
  • Samina Ejaz Syed7
  • Shufang Liang1
7 affiliations
  1. 1Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu China
  2. 2Department of Central Laboratory NHC Key Laboratory of Pulmonary Immunological Diseases Guizhou Provincial People's Hospital Guiyang China
  3. 3Department of Neurology Second Affiliated Hospital of Army Medical University (Xinqiao Hospital) Chongqing China
  4. 4Department of Medical Oncology Cancer Center West China Hospital Sichuan University Chengdu China
  5. 5Department of Gastrointestinal Surgery West China Hospital Sichuan University Chengdu China
  6. 6The Second Department of Gastrointestinal Surgery the Affiliated Hospital of North Sichuan Medical College Sichuan China
  7. 7Department of Biochemistry and Biotechnology Baghdad Campus The Islamia University of Bahawalpur Bahawalpur Pakistan
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Abstract

DDX3 has dual biological functions of regulating cell proliferation and antiviral effects. Herein, we focus on SUMOylation‐mediated DDX3 in the interplay from hepatitis B virus (HBV) infection to HBV‐associated hepatocellular carcinoma (HBV‐HCC) progression. We identified dynamic regulation of SUMOylation and DeSUMOylation of DDX3 at four key lysine (K) residues (K81/K208/K215/K564) in response to HBV infection. During the early stage of HBV acute infection, SENP1 interacts with DDX3 to keep DDX3 deSUMOylation for inhibiting HBV replication. During persistent HBV replication, as SENP1 downregulation and HBV polymerase accumulation, DDX3 disassociates with SENP1 to bind with TRIM28, which induces DDX3 SUMOylation. Meanwhile, SUMOylated DDX3 enhances alternative splicing of KLF4 mRNAs to generate KLF4α isoform that involves in Cyclin D1‐mediated cell cycle progression, weakens tumor suppressor function of DDX3 and promotes HBV‐HCC. Moreover, DDX3 expression is positively correlated with KLF4 mRNA, and high DDX3 level with low TRIM28 expression indicates a better overall survival for HBV‐HCC patients. Our findings reveal the dynamic regulation between SUMOylation and deSUMOylation of DDX3, including mediating HBV gene transcription, virus antigen secretion, and cell proliferation. Furthermore, the TRIM28‐DDX3‐KLF4 axis as a novel therapeutic target for HBV‐HCC, exhibiting the dual ability to inhibit tumor progression and disrupt the HBV–host interaction.

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Cite

BibTeXRIS
BibTeX
@article{yang2026sumoylated,
  title = {{SUMOylated DDX3 Promotes HBV Replication and Tumor Growth of Hepatocellular Carcinoma via TRIM28‐DDX3‐KLF4α Signaling Axis}},
  author = {Yanfang Yang and Ting Kong and Binghan Wang and Xiaoli Jin and Lan Huang and Nan Zhang and Siyu Tang and Samina Ejaz Syed and Shufang Liang},
  journal = {Advanced Science},
  year = {2026},
  month = nov,
  doi = {10.1002/advs.78603},
  url = {https://doi.org/10.1002/advs.78603},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - SUMOylated DDX3 Promotes HBV Replication and Tumor Growth of Hepatocellular Carcinoma via TRIM28‐DDX3‐KLF4α Signaling Axis
AU  - Yanfang Yang
AU  - Ting Kong
AU  - Binghan Wang
AU  - Xiaoli Jin
AU  - Lan Huang
AU  - Nan Zhang
AU  - Siyu Tang
AU  - Samina Ejaz Syed
AU  - Shufang Liang
PY  - 2026
DA  - 2026/11/03
JO  - Advanced Science
DO  - 10.1002/advs.78603
UR  - https://doi.org/10.1002/advs.78603
AB  - DDX3 has dual biological functions of regulating cell proliferation and antiviral effects. Herein, we focus on SUMOylation‐mediated DDX3 in the interplay from hepatitis B virus (HBV) infection to HBV‐associated hepatocellular carcinoma (HBV‐HCC) progression. We identified dynamic regulation of SUMOylation and DeSUMOylation of DDX3 at four key lysine (K) residues (K81/K208/K215/K564) in response to HBV infection. During the early stage of HBV acute infection, SENP1 interacts with DDX3 to keep DDX3 deSUMOylation for inhibiting HBV replication. During persistent HBV replication, as SENP1 downregulation and HBV polymerase accumulation, DDX3 disassociates with SENP1 to bind with TRIM28, which induces DDX3 SUMOylation. Meanwhile, SUMOylated DDX3 enhances alternative splicing of KLF4 mRNAs to generate KLF4α isoform that involves in Cyclin D1‐mediated cell cycle progression, weakens tumor suppressor function of DDX3 and promotes HBV‐HCC. Moreover, DDX3 expression is positively correlated with KLF4 mRNA, and high DDX3 level with low TRIM28 expression indicates a better overall survival for HBV‐HCC patients. Our findings reveal the dynamic regulation between SUMOylation and deSUMOylation of DDX3, including mediating HBV gene transcription, virus antigen secretion, and cell proliferation. Furthermore, the TRIM28‐DDX3‐KLF4 axis as a novel therapeutic target for HBV‐HCC, exhibiting the dual ability to inhibit tumor progression and disrupt the HBV–host interaction.
SN  - 2198-3844
ER  -