UBAP2 contributes to radioresistance by enhancing homologous recombination through SLC27A5 ubiquitination in hepatocellular carcinoma.

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  • Author(s): Liu Z;Liu Z; Yuan J; Yuan J; Yuan J; Zeng Q; Zeng Q; Zeng Q; Wu Z; Wu Z; Han J; Han J
  • Source:
    Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Dec; Vol. 1870 (8), pp. 167481. Date of Electronic Publication: 2024 Aug 24.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-260X (Electronic) Linking ISSN: 09254439 NLM ISO Abbreviation: Biochim Biophys Acta Mol Basis Dis Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier
    • Subject Terms:
      Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/metabolism ; Carcinoma, Hepatocellular*/radiotherapy ; Liver Neoplasms*/genetics ; Liver Neoplasms*/pathology ; Liver Neoplasms*/radiotherapy ; Liver Neoplasms*/metabolism ; Radiation Tolerance*/genetics ; Ubiquitination*; Humans ; Mice ; Animals ; Homologous Recombination ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; Prognosis ; Rad51 Recombinase/metabolism ; Rad51 Recombinase/genetics ; Cell Proliferation/genetics ; Amino Acid Transport Systems, Neutral/genetics ; Amino Acid Transport Systems, Neutral/metabolism ; Mice, Nude ; Male ; Carrier Proteins
    • Abstract:
      Radiotherapy stands as an effective method in the clinical treatment of hepatocellular carcinoma (HCC) patients. However, both primary and acquired radioresistance limit its clinical application in HCC. Therefore, investigating the mechanism of radioresistance may provide other options for treating HCC. Based on single-cell RNA sequencing (scRNA-seq) and HCC transcriptome datasets, 227 feature genes with prognostic value were selected to establish the tSNE score. The tSNE score emerged as an independent prognostic factor for HCC and correlated with cell proliferation and radioresistance-related biological functions. UBAP2 was identified as the most relevant gene with the tSNE score, consistently elevated in human HCC samples, and positively associated with patient prognosis. Functionally, UBAP2 knockdown impeded HCC development and reduced radiation resistance in vitro and in vivo. The ectopic expression of SLC27A5 reversed the effects of UBAP2. Mechanically, we uncovered that UBAP2, through the ubiquitin-proteasome system, decreased the homologous recombination-related gene RAD51, not the non-homologous end-joining (NHEJ)-related gene CTIP, by degrading the antioncogene SLC27A5, thereby generating radioresistance in HCC. The findings recapitulated that UBAP2 promoted HCC progression and radioresistance via SLC27A5 stability mediated by the ubiquitin-proteasome pathway. It was also suggested that targeting the UBAP2/SLC27A5 axis could be a valuable radiosensitization strategy in HCC.
      Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Hepatocellular carcinoma; Radiosensitivity; UBAP2; Ubiquitination; tSNE score
    • Accession Number:
      0 (Ubap2L protein, human)
      EC 2.7.7.- (Rad51 Recombinase)
      0 (Amino Acid Transport Systems, Neutral)
      EC 2.7.7.- (RAD51 protein, human)
      0 (Carrier Proteins)
    • Publication Date:
      Date Created: 20240826 Date Completed: 20240918 Latest Revision: 20240919
    • Publication Date:
      20240920
    • Accession Number:
      10.1016/j.bbadis.2024.167481
    • Accession Number:
      39186963