Histone-related gene WDR77 promotes tumor progression through cell cycle regulation in skin cutaneous melanoma.

BACKGROUND

Skin cutaneous melanoma (SKCM) is extremely malignant, leading to poor prognosis. Epigenetic dysregulation, particularly histone modifications, contributes to disease progression. However, effective histone-based prognostic biomarkers are still lacking in clinical practice.

METHODS

Transcriptomic data from TCGA-SKCM and five GEO datasets were analyzed. Ten machine learning algorithms were integrated to build 101 prognostic models. The optimal model, based on seven histone-related genes, showed the highest C-index and was validated in both training and validation cohorts. WDR77 was identified as the hub gene by random forest analysis. The expression of WDR77 was profiled in SKCM. Survival analysis, pathway enrichment analyses, single-cell and spatial transcriptomics were performed to investigate the role of WDR77 in SKCM. The therapeutic relevance of WDR77 was also investigated. In vitro experiments were conducted to validate the function of WDR77.

RESULTS

WDR77, a histone methylation factor working with PRMT5, was identified as a key candidate. WDR77 was significantly upregulated in SKCM and correlated with poor clinical outcomes. Pathway analysis showed that WDR77 was primarily associated with cell-cycle dysregulation. CDC20, a cell cycle factor, emerged as a key co-expressed gene. Patients with concurrent high expression of WDR77 and CDC20 had the worst survival outcomes. WDR77 was predominantly expressed in malignant cells across pan-cancer datasets and positively correlated with CDC20. Spatial transcriptomics confirmed their co-localization and co-upregulation in tumor regions. Functional experiments demonstrated that WDR77 promotes proliferation, migration, and cell cycle progression. Overexpression of WDR77 also increased CDC20 protein levels.

CONCLUSION

WDR77 serves as both a prognostic biomarker and functional regulator in melanoma, highlighting its potential as a therapeutic target.