ILF3 Regulates Cell Proliferation and Metastasis by Competitively Antagonizing the Interaction Between HMGCL and USP38 in Hepatocellular Carcinoma

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Abstract
Background: Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. Previous studies have reported that interleukin enhancer–binding factor 3 (ILF3) is involved in the regulation of multiple cancers. This study investigated the molecular mechanisms whereby ILF3 promotes HCC progression. Methods: ILF3 expression levels were determined through immunohistochemistry (IHC) and Western blot (WB) analyses. The biological functions of ILF3 in HCC were evaluated using both in vitro assays and in vivo animal models. Co‐immunoprecipitation (Co‐IP) was carried out to identify HMGCL as a binding partner of ILF3. To clarify the potential molecular pathways underlying ILF3‐mediated regulation of HCC malignant behaviors, protein stability assays and in vitro ubiquitination experiments were performed. Results: ILF3 was significantly upregulated in HCC. The patients with high expression of ILF3 showed poor prognosis in our cohort. ILF3 knockdown inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo in this study. Mechanistically, ILF3 was found to be bound to HMGCL and to accelerate its protein degradation. Additionally, we found that ILF3 promotes HCC cell proliferation and metastasis through HMGCL. Overexpression of HMGCL in ILF3‐upregulated HCC cells could significantly reverse the proliferation and invasion role of ILF3 on HCC cells. Moreover, USP38 was identified as a deubiquitinating enzyme that participates in promoting the stability of HMGCL. ILF3 disrupted the interaction between USP38 and HMGCL, thereby enhancing HMGCL ubiquitination and accelerating its degradation. Conclusion: ILF3 promotes the proliferation and metastasis of HCC by enhancing the ubiquitination of HMGCL by interfering with the interaction between the deubiquitinase USP38 and HMGCL.
Funding Information
  • Natural Science Foundation of Hunan Province (W202443286)
  • Natural Science Foundation of Hunan Province (2025JJ60776)
  • National Natural Science Foundation of China (82460489)

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