title: Expression of Id-1 is regulated by MCAM/MUC18: a missing link in melanoma progression.
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.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Zigler
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Villares
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Russell R
authors.initials: RR
authors.lastname: Braeuer
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kamiya
authors.forename: Vladislava O
authors.initials: VO
authors.lastname: Melnikova
authors.forename: Renduo
authors.initials: R
authors.lastname: Song
authors.forename: Ran
authors.initials: R
authors.lastname: Friedman
authors.forename: Rhoda M
authors.initials: RM
authors.lastname: Alani
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D051929:CD146 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D051929:CD146 Antigen; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1