Ganlu Deng

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.

Colorectal cancer (CRC) is a common cancer and leading cause of cancer-related death with an insidious onset and a high recurrence rate after surgery. Autophagy has been shown to be closely related to the progression of CRC. This study aimed to identify novel biomarkers based on autophagy-related genes (ATGs). RNA-sequencing and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database, and combined with ATG data to identify differentially expressed autophagy-related genes (DEATGs). A prognostic risk model of the DEATGs was constructed using multivariable Cox regression. Genomic alteration, DNA methylation, and the tumor mutational burden (TMB) of the hub ATGs were analyzed, along with pan-cancer expression, interaction proteins, prognostic values, pharmaceutical sensitivity, and immune infiltration. The expression of the hub ATGs was verified in local CRC samples and cell lines. Functional assays were performed. The expression of autophagy-related proteins was detected. A total of 320 DEATGs were identified, and a two-gene prognostic signature (comprising WDR45 and EGFR) was developed. The hub ATG WDR45 was highly expressed in various cancers and acted as an independent predictor of CRC. WDR45 expression was associated with putative genetic alterations, TP53 mutations, promoter methylation, and the TMB. WDR45 expression was also negatively correlated with the sensitivity of 74 anti-cancer drugs. WDR45 was closely related to the infiltration of regulatory T cells (Tregs), CD4⁺ T cells, and macrophages. The aberrant upregulation of WDR45 in CRC was confirmed in 46 paired tissue specimens and five cell lines. The knockdown of WDR45 suppressed the proliferation of CRC cells, and inhibited cell autophagy. This study constructed an ATG-based signature that accurately predicted the prognosis of CRC patients. It also identified WDR45 as a novel biomarker and target for CRC.