Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases

Despite remarkable advances in treating patients with metastatic melanoma, the management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an impor-tant mechanism for the adaptation of melanoma cells to the brain environment. In this study, the methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared with extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. In accordance with the underlying promoter methylation and gene expression changes, a significantly different protein expression was confirmed for STK10, PDXK, WDR24, CSSP1, NMB, RASL11B, phosphorylated PRKCZ, PRKCZ, and phosphorylated GRB10 in the intracranial metastases. The observed changes imply a distinct intracranial phenotype with increased protein kinase B phosphorylation and a higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of phosphorylated protein kinase B and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant al-terations were identified that provide insights into the molecular mechanisms that discriminate brain metas-tases from other organ metastases, which could be exploited by targeting the affected signaling pathways.

Automated summary

This study integrated omics data analysis to evaluate the methylomes and transcriptomes of matched melanoma metastases, identifying 38 candidate genes with distinct promoter methylation and gene expression changes in intracranial compared with extracranial metastases. The protein expression of the 11 most promising genes was validated using immunohistochemistry, and significant differences were observed in intracranial metastases. Knockdown of PRKCZ or GRB10 altered protein kinase B expression and decreased the viability of a brain-specific melanoma cell line. These findings provide insights into the molecular mechanisms that differentiate brain metastases and could be targeted for therapy.