title: Heterogeneous expression and functional relevance of the ubiquitin carboxyl-terminal hydrolase L1 in melanoma.
abstract: The expression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is deregulated in human cancer cells with tumor inhibiting or promoting functions. Due to less knowledge on the role of UCHL1 in melanoma progression, the expression pattern and function of UCHL1 as well as the deregulated signaling pathways were characterized. A large number of melanoma cell lines, tissue microarrays of melanoma lesions and control tissues were analyzed for UCHL1 expression using PCR, Western blot and/or immunohistochemistry. The analysis revealed that melanocyte cultures, 24 of 331 melanoma lesions, two of 18 short-term cultures and two of 19 melanoma cell lines tested, respectively, heterogeneously expressed UCHL1. The low frequency of UCHL1 expression in melanoma cells was due to gene silencing by promoter DNA hypermethylation. Using different transfection models an enzyme activity-dependent growth promoting function of UCHL1 via the activation of the mitogen-activated protein kinase signaling pathway was found in melanoma cells. Under oxygen stress a dose-dependent effect of UCHL1 was detected, which was mediated by a dynamic modification of the PI3K-Akt signaling. Thus, the aberrant UCHL1 expression in melanoma cells is linked to dynamic changes in growth properties and signal transduction cascades suggesting that UCHL1 provides a novel marker and/or therapeutic target at least for a subset of melanoma patients.
authors.affiliation: Martin Luther University Halle-Wittenberg, Institute of Medical Immunology, 06112, Halle (Saale), Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wulfänger
authors.forename: Katharina
authors.initials: K
authors.lastname: Biehl
authors.forename: Anja
authors.initials: A
authors.lastname: Tetzner
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.forename: Stefanie
authors.initials: S
authors.lastname: Meyer
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D025801:Ubiquitin; C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D043222:Ubiquitin Thiolesterase
keywords: UCHL1; biomarker; melanoma; ubiquitination