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. 2025 Jul 29;21(7):e1011788.
doi: 10.1371/journal.pgen.1011788. eCollection 2025 Jul.

Identification of hub gene associated with colorectal cancer: Integrating Mendelian randomization, transcriptome analysis and experimental verification

Yu Zhang  1   2 , Xu Han  1 , Yichun Yang  1 , Jiayan Ren  1 , Zixi Zhang  2 , Yanmin Zhang  1 , Qi Su  1 , Dake Chu  3
Affiliations

Identification of hub gene associated with colorectal cancer: Integrating Mendelian randomization, transcriptome analysis and experimental verification

Yu Zhang et al. PLoS Genet. .

Abstract

Background: Colorectal cancer (CRC) is a prevalent malignancy with significant mortality rates globally. Understanding the genetic and molecular mechanisms underlying CRC development is crucial for improving therapeutic strategies.

Method: In this study, we utilized cis-eQTL summary data to identify genes potentially causally associated with CRC. The expression levels of candidate genes in tumor and normal tissues were compared using the GEPIA2 database. The correlations between FUT8 expression and cellular functions, tumor mutation burden, immune checkpoint genes, and immune infiltration were analyzed. Molecular docking was performed to identify potential drugs targeting FUT8, and the effects of the selected drug on cell proliferation were evaluated using the MTT assay. Additionally, the cellular thermal shift assay (CETSA) was employed to assess the interaction between the drug and the target protein.

Results: We identified 19 genes with eQTLs potentially associated with CRC, among which six eQTLs were associated with increased CRC risk, including FUT8. FUT8 was significantly overexpressed in CRC tumor tissues and correlated with various cellular functions such as stemness, invasion, EMT, and metastasis. Higher FUT8 expression was associated with higher tumor mutation burden and significant correlations with multiple immune checkpoint genes. Molecular docking identified VE-822 as a promising drug candidate targeting FUT8, which demonstrated inhibitory effects on CRC cell proliferation. The CETSA results indicated that VE ‒ 822 could bind to FUT8 and improve its thermal stability.

Conclusion: FUT8 is a crucial gene that causes colon cancer and is linked to tumour immunity. VE-822 is a promising candidate for treating CRC by targeting FUT8.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Positive eQTLs potentially causally associated with CRC.
Fig 2
Fig 2. FUT8 expression levels and localization.
A: The expression difference of related genes between CRC tumor tissue and normal tissue. B: Correlation between gene expression and clinical stage. C: Immunohistochemical observation of FUT8 in CRC tissues (n = 3). Immunohistochemical results of FUT8 protein were obtained from HPA database.
Fig 3
Fig 3. Expression of FUT8 at the cellular level and its correlation with cellular functions.
A: Single-cell expression of FUT8 in different CRC cohorts. B: Potential correlation of FUT8 with four cellular functions in CRC cells.
Fig 4
Fig 4. Correlation of FUT8 with tumor mutation burden and immune checkpoints.
A: Tumor mutation burden scoring in the TCGA CRC dataset. B: Study on the correlation of FUT8 with tumor mutation burden. C: Co-expression analysis of FUT8 with 79 immune checkpoint genes.
Fig 5
Fig 5. Impact of FUT8 expression on immune infiltration in CRC.
Fig 6
Fig 6. Experimental validation of the core targets.
A: Molecular docking results of FUT8 with VE-822. B: Chemical structure of VE-822. C: Inhibitory effect of VE-822 on colon cancer cells. D: Differences in FUT8 between normal and colon cancer cells. E: The binding ability of VE-822 to FUT8 was verified by cellular thermal shift assay. *P < 0.05; **P < 0.01, ***P < 0.001.
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