Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma

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• 作者：Phil F Cheng (1)
  Olga Shakhova (3)
  Daniel S Widmer (1)
  Ossia M Eichhoff (1)
  Daniel Zingg (3)
  Sandra C Frommel (4)
  Benedetta Belloni (1)
  Marieke IG Raaijmakers (1)
  Simone M Goldinger (1)
  Raffaella Santoro (4)
  Silvio Hemmi (2)
  Lukas Sommer (3)
  Reinhard Dummer (1)
  Mitchell P Levesque (1)
  
  1. Department of Dermatology ; Faculty of Medicine ; University Hospital Z眉rich ; and University of Z眉rich ; Wagistrasse 14 ; CH-8952 ; Z眉rich ; Switzerland
  3. Cell and Developmental Biology ; Institute of Anatomy ; University of Z眉rich ; Z眉rich ; Switzerland
  4. Institute of Veterinary Biochemistry and Molecular Biology ; University of Z眉rich ; Z眉rich ; Switzerland
  2. Faculty of Mathematics and Natural Sciences ; Institute of Molecular Life Sciences ; University of Z眉rich ; Z眉rich ; Switzerland
  
• 刊名：Genome Biology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：16
• 期：1
• 全文大小：2,246 KB
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• 刊物主题：Animal Genetics and Genomics; Human Genetics; Plant Genetics & Genomics; Microbial Genetics and Genomics; Fungus Genetics; Bioinformatics;
• 出版者：BioMed Central
• ISSN：1465-6906

文摘

Background Melanoma is the most fatal skin cancer displaying a high degree of molecular heterogeneity. Phenotype switching is a mechanism that contributes to melanoma heterogeneity by altering transcription profiles for the transition between states of proliferation/differentiation and invasion/stemness. As phenotype switching is reversible, epigenetic mechanisms, like DNA methylation, could contribute to the changes in gene expression. Results Integrative analysis of methylation and gene expression datasets of five proliferative and five invasion melanoma cell cultures reveal two distinct clusters. SOX9 is methylated and lowly expressed in the highly proliferative group. SOX9 overexpression results in decreased proliferation but increased invasion in vitro. In a B16 mouse model, sox9 overexpression increases the number of lung metastases. Transcriptional analysis of SOX9-overexpressing melanoma cells reveals enrichment in epithelial to mesenchymal transition (EMT) pathways. Survival analysis of The Cancer Genome Atlas melanoma dataset shows that metastatic patients with high expression levels of SOX9 have significantly worse survival rates. Additional survival analysis on the targets of SOX9 reveals that most SOX9 downregulated genes have survival benefit for metastatic patients. Conclusions Our genome-wide DNA methylation and gene expression study of 10 early passage melanoma cell cultures reveals two phenotypically distinct groups. One of the genes regulated by DNA methylation between the two groups is SOX9. SOX9 induces melanoma cell invasion and metastasis and decreases patient survival. A number of genes downregulated by SOX9 have a negative impact on patient survival. In conclusion, SOX9 is an important gene involved in melanoma invasion and negatively impacts melanoma patient survival.