Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases

Despite remarkable advances in treating patients with metastatic melanoma, management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, 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 to extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. For 8 of them, STK10, PDXK, WDR24, CSPP1, NMB, RASL11B, pPRKCZ/PRKCZ, pGRB10, a significantly different protein expression in intracranial versus extracranial metastases was confirmed in accordance with the underlying promoter methylation and gene expression changes. The observed changes imply a distinct intracranial phenotype with increased AKT phosphorylation and higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of pAKT and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified, that provide insights into the molecular mechanisms that discriminate brain from other organ metastases, which could be exploited by targeting the affected signaling pathways.