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Transcriptomic profiling of CRISPR-Cas9 knockout of RAD51D, LIMCH1, and BRD9 in MC38 colorectal cancer cells reveals regulation of PD-L1 expression

ABSTRACT: Programmed death-ligand 1 (PD-L1) expression in tumor cells plays a critical role in regulating anti-tumor immune responses and determining the efficacy of immune checkpoint blockade therapy. Previous studies have suggested that multiple genes are associated with PD-L1 expression in colorectal cancer, but the underlying regulatory mechanisms remain incompletely understood. In this study, we investigated the transcriptional consequences of knocking out three candidate genes, RAD51D, LIMCH1, and BRD9, which were previously identified to be associated with PD-L1 expression in colorectal cancer. Using the murine colorectal cancer cell line MC38, we generated CRISPR-Cas9–mediated knockout cell lines targeting each gene and performed RNA sequencing to characterize the global transcriptomic alterations. Our results revealed that RAD51D deficiency led to activation of the JAK1–STAT1 signaling pathway, accompanied by increased expression of JAK1, STAT1, and IRF1, which are known transcriptional regulators of PD-L1. Consistently, PD-L1 transcription was upregulated following RAD51D knockout. Similar transcriptomic analyses were performed for LIMCH1 and BRD9 knockout cells to explore their potential regulatory roles in PD-L1 expression and tumor immune signaling. This dataset provides a comprehensive transcriptomic resource for understanding how these genes regulate PD-L1 expression and immune-related signaling pathways in colorectal cancer cells, and may facilitate further studies on the molecular mechanisms underlying tumor immune evasion and responses to immune checkpoint blockade.

ORGANISM(S): Mus musculus

PROVIDER: GSE324386 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.

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Transcriptomic profiling of CRISPR-Cas9 knockout of RAD51D, LIMCH1, and BRD9 in MC38 colorectal cancer cells reveals regulation of PD-L1 expression

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