BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma

• Published in: BMC cancer 2013-08, Vol.13 (1), p.371-371, Article 371
• Main Authors: Matatall, Katie A, Agapova, Olga A, Onken, Michael D, Worley, Lori A, Bowcock, Anne M, Harbour, J William
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Animal experimentation; Animals; Cancer; Cell Cycle - genetics; Cell differentiation; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cluster Analysis; Disease Models, Animal; Experiments; Gene expression; Gene Expression Profiling; Genetic aspects; Genomes; Genotype & phenotype; Heterografts; Host Cell Factor C1 - metabolism; Humans; Insects; Liver Neoplasms - secondary; Male; Medicine; Melanocytes; Melanocytes - metabolism; Melanocytes - pathology; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastasis; Mice; Mutation; Neoplastic Stem Cells - metabolism; Phenotype; Protein Binding; Reproducibility of Results; RNA Interference; Stem cells; Studies; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Ubiquitin Thiolesterase - deficiency; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Uvea; Uveal Neoplasms - genetics; Uveal Neoplasms - metabolism; Uveal Neoplasms - pathology
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-13-371

Uveal melanoma is a highly aggressive cancer with a strong propensity for metastasis, yet little is known about the biological mechanisms underlying this metastatic potential. We recently showed that most metastasizing uveal melanomas, which exhibit a class 2 gene expression profile, contain inactivating mutations in the tumor suppressor BAP1. The aim of this study was to investigate the role of BAP1 in uveal melanoma progression. Uveal melanoma cells were studied following RNAi-mediated depletion of BAP1 using proliferation, BrdU incorporation, flow cytometry, migration, invasion, differentiation and clonogenic assays, as well as in vivo tumorigenicity experiments in NOD-SCID-Gamma mice. Depletion of BAP1 in uveal melanoma cells resulted in a loss of differentiation and gain of stem-like properties, including expression of stem cell markers, increased capacity for self-replication, and enhanced ability to grow in stem cell conditions. BAP1 depletion did not result in increased proliferation, migration, invasion or tumorigenicity. BAP1 appears to function in the uveal melanocyte lineage primarily as a regulator of differentiation, with cells deficient for BAP1 exhibiting stem-like qualities. It will be important to elucidate how this effect of BAP1 loss promotes metastasis and how to reverse this effect therapeutically.