title: Deregulation of protein methylation in melanoma.
abstract: Loss of methylthioadenosine phosphorylase (MTAP) expression and a concomitant accumulation of 5'-methyl-thioadenosine (MTA) characterise several tumour entities including malignant melanoma. MTA affects cellular signalling, proliferation and migration not only of cancer but also surrounding cells including lymphocytes and stromal fibroblasts. The mode of action of MTA is still not known. Interestingly, MTA is a known potent inhibitor of protein arginine methyltransferases (PRMTs) and is used as a tool in studying activity and impact of PRMTs. This study aimed at analysing PRMTs in melanoma and the potential impact of MTA on tumourigenesis. Our findings demonstrate that expression of PRMT4/CARM1 and PRMT6 is deregulated in melanoma, whereas expression of the remaining PRMTs stays unchanged. General PRMT activity and, consequently, symmetric and asymmetric protein methylation are reduced significantly in melanoma cells and tissues. This is due to a loss of MTAP expression and accumulation of MTA. Reduction of protein methylation by MTA affects cell signalling and leads, for example, to an activation of extracellular signal-regulated kinase (ERK) activity. The effects of endogeneous MTA on PRMTs as presented in this study can strongly support the migratory and invasive phenotype of melanoma cells.
authors.affiliation: Institute of Pathology, University of Regensburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Limm
authors.forename: Corinna
authors.initials: C
authors.lastname: Ott
authors.forename: Susanne
authors.initials: S
authors.lastname: Wallner
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Mueller
authors.forename: Peter
authors.initials: P
authors.lastname: Oefner
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D001120:Arginine / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013872:Thionucleosides / Q000378:metabolism
chemical_list: D003839:Deoxyadenosines; D009687:Nuclear Proteins; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D001120:Arginine; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D048049:Extracellular Signal-Regulated MAP Kinases