Expression of Id-1 is regulated by MCAM/MUC18: A missing link in melanoma progression

Maya Zigler, Gabriel J. Villares, Andrey S. Dobroff, Hua Wang, Li Huang, Russell R. Braeuer, Takafumi Kamiya, Vladislava O. Melnikova, Renduo Song, Ran Friedman, Rhoda M. Alani, Menashe Bar-Eli

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The acquisition of the metastatic melanoma phenotype is associated with increased expression of the melanoma cell adhesion molecule MCAM/MUC18 (CD146). However, the mechanism by which MUC18 contributes to melanoma metastasis remains unclear. Herein, we stably silenced MUC18 expression in two metastatic melanoma cell lines, A375SM and C8161, and conducted cDNA microarray analysis. We identified and validated that the transcriptional regulator, inhibitor of DNA binding-1 (Id-1), previously shown to function as an oncogene in several malignancies, including melanoma, was downregulated by 5.6-fold following MUC18 silencing. Additionally, we found that MUC18 regulated Id-1 expression at the transcriptional level via ATF-3, which itself was upregulated by 6.9-fold in our cDNA microarray analysis. ChIP analysis showed increased binding of ATF-3 to the Id-1 promoter after MUC18 silencing. To complement these studies, we rescued the expression of MUC18, which reversed the expression patterns of Id-1 and ATF-3. Moreover, we showed that MUC18 promotes melanoma invasion through Id-1, as overexpression of Id-1 in MUC18-silenced cells resulted in increased MMP-2 expression and activity. To our knowledge, this is the first demonstration that MUC18 is involved in cell signaling regulating the expression of Id-1 and ATF-3, thus contributing to melanoma metastasis.

Original languageEnglish (US)
Pages (from-to)3494-3504
Number of pages11
JournalCancer research
Volume71
Issue number10
DOIs
StatePublished - May 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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