title: RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells.
abstract: Brain metastasis is a major contributor to cancer mortality, yet, the genetic changes underlying the development of this capacity remain poorly understood. RASSF proteins are a family of tumor suppressors that often suffer epigenetic inactivation during tumorigenesis. However, their epigenetic status in brain metastases has not been well characterized. We have examined the promoter methylation of the classical RASSF members (RASSF1A-RASSF6) in a panel of metastatic brain tumor samples. RASSF1A and RASSF2 have been shown to undergo promoter methylation at high frequency in primary lung and breast tumors and in brain metastases. Other members exhibited little or no methylation in these tumors. In examining melanoma metastases, however, we found that RASSF6 exhibits the highest frequency of inactivation in melanoma and in melanoma brain metastases. Most melanomas are driven by an activating mutation in B-Raf. Introduction of RASSF6 into a B-Raf(V600E)-containing metastatic melanoma cell line inhibited its ability to invade through collagen and suppressed MAPK pathway activation and AKT. RASSF6 also appears to increase the association of mutant B-Raf and MST1, providing a potential mechanism by which RASSF6 is able to suppress MAPK activation. Thus, we have identified a novel potential role for RASSF6 in melanoma development. Promoter methylation leading to reduced expression of RASSF6 may play an important role in melanoma development and may contribute to brain metastases.
authors.affiliation: a Departments of Biochemistry/Pharmacology Toxicology ; University of Louisville ; Louisville, KY USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Mezzanotte
authors.forename: Victoria
authors.initials: V
authors.lastname: Hill
authors.forename: M Lee
authors.initials: ML
authors.lastname: Schmidt
authors.forename: Thoraia
authors.initials: T
authors.lastname: Shinawi
authors.forename: Stella
authors.initials: S
authors.lastname: Tommasi
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D051017:Apoptosis Regulatory Proteins; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; C425300:RASSF2 protein, human; C519911:RASSF6 protein, human; D025521:Tumor Suppressor Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020559:Monomeric GTP-Binding Proteins
keywords: MAPK; RASSF; Ras; brain metastases; invasion; melanoma