BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma
Open Access
- 5 August 2013
- journal article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 13 (1), 371
- https://doi.org/10.1186/1471-2407-13-371
Abstract
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.Keywords
This publication has 35 references indexed in Scilit:
- ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensityPigment Cell & Melanoma Research, 2011
- The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cellsNature Genetics, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Deregulated expression of Polycomb-group oncogenes in human malignant lymphomas and epithelial tumorsHuman Molecular Genetics, 2005
- Gene Expression Profiling in Uveal Melanoma Reveals Two Molecular Classes and Predicts Metastatic DeathCancer Research, 2004
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003
- Lentivirus-delivered stable gene silencing by RNAi in primary cellsRNA, 2003
- Significance analysis of microarrays applied to the ionizing radiation responseProceedings of the National Academy of Sciences of the United States of America, 2001
- Centrosome Amplification and a Defective G2–M Cell Cycle Checkpoint Induce Genetic Instability in BRCA1 Exon 11 Isoform–Deficient CellsMolecular Cell, 1999
- BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppressionOncogene, 1998