Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis

• DOI: 10.18632/oncotarget.14042
• Publication Date: 2016-12-22T16:29:38Z
• Authors: Aniruddha Chatterjee; Peter A Stockwell; Antonio Ahn; Euan J Rodger; Anna L Leichter; Michael R Eccles
• Keywords: 0301 basic medicine; Skin Neoplasms; Sequence Analysis, DNA; DNA Methylation; Epigenesis, Genetic; Up-Regulation; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Melanoma, Cutaneous Malignant; Cell Line, Tumor; Humans; CpG Islands; Neoplasm Metastasis; Promoter Regions, Genetic; Melanoma; Research Paper; Transcription Factors

Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, studies metastasis-related epigenetic drivers, part because a framework for identifying driver changes metastasis has not established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns three cutaneous primary and metastatic melanoma cell line pairs identify drivers. Globally, lines were hypomethylated compared the matched lines. whole genome RRBS 75 shared (10 hyper- 65 hypomethylated) differentially methylated fragments (DMFs), which associated with 68 genes showing significant differences. One gene, Early B Cell Factor 3 (EBF3), exhibited promoter hypermethylation lines, was validated two publicly available independent cohorts (n = 40 458 melanomas, respectively). We found that EBF3 increased mRNA levels melanomas subsequent inhibition expression. RNAi-mediated knockdown decreased proliferation, migration invasion Overall, numerous characterising including EBF3-induced aggressive phenotypic behaviour elevated expression melanoma, suggesting may be candidate