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The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell invasion

ABSTRACT: The transcription factor SRY(sex related protein-Y)-box10 (SOX10) plays a key role in the development of melanocytes and peripheral glial cells from neural crest precursors. Recently, we and other groups found SOX10 to be involved in melanoma initiation, proliferation, invasion, and survival. However, specific mediators which impart the oncogenic role of SOX10 in melanoma remain widely unknown. To identify potential target genes of SOX10, we performed RNA sequencing to analyze genome-wide expression alterations after ectopic expression of SOX10. Among nine genes differentially regulated by SOX10, only peripheral myelin protein 2 (PMP2) was found upregulated in several other melanoma cell lines. PMP2 is one of the most abundant myelin proteins in glial cells and is necessary for the formation and maintenance of the myelin sheath. We detected PMP2 expression in a subset of human melanoma cell lines while it was absent in human melanocytes and fibroblasts. Direct binding of SOX10 to the PMP2 promoter was shown by chromatin immunoprecipitation and electrophoretic shift assay. In three-dimensional spheroid assays, we found that PMP2 overexpression increased melanoma cell invasion. In conclusion, we identified PMP2 as target gene of SOX10 and propose a novel role for PMP2 in melanoma cell invasion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79988 | GEO | 2017/12/31

SECONDARY ACCESSION(S): PRJNA317571

REPOSITORIES: GEO

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Project description:It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNA specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 are likely to be involved in migration and metastasis of melanoma cells. We carried out microarray-based gene expression profiling using Sox10-specific siRNA to identify regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1R) partake in the regulation of migration. We provide evidences that a significant portion of the effect of Sox10 on migration is mediated by Mitf, a transcription factor downstream to Sox10. The involvement of Mc1R in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represent potential targets of therapeutic intervention. Chemically synthesized siRNA duplex (WT1-Sox10) was used to knock-down the transcription factor Sox10 in murine melanoma cell line B16F10. For the control, siRNA containing 5 nucleotide alterations (MT1-Sox10) were used. Total RNA was subsequently prepared to synthesize probes for microarray screening. A total of three pairs of replicate samples were generated each from separate transfection followed by RNA preparation. Expression values were determined and compared within each pair of WT1-Sox10 and MT1-Sox10 transfections. Genes showing over 2 fold changes in all three replicate pairs were subjected to subsequent analyses.

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The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell invasion

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