Mind the BAP

Abstract

Efforts to understand the genetics of uveal melanoma are being spurred on by the rapid translation of mutational findings to clinically effective, targeted therapies in its cutaneous counterpart. However, gene mutations that are frequent in cutaneous melanoma, such as B-RAF, are rarely found in uveal melanoma. Thus, the ‘genetic smoking guns’ associated with uveal melanoma have remained unidentified until recent discoveries. Studies have uncovered mutually exclusive mutations in G protein-coupled receptor α-subunits, GNAQ and GNA11, in 83% of uveal melanomas (Van Raamsdonk et al., 2010 and references therein). Additionally, a report from the Harbour and Bowcock laboratories (discussed in this News and Views) implicates alterations in the gene encoding BRCA1-associated protein 1 (BAP1) in the progression of uveal melanoma. Harbour et al. performed exome capture/deep sequencing analysis of genes on chromosome 3. This region has been intensively scrutinized based on previous evidence associating monosomy of chromosome 3 with the more aggressive, class 2 subtype of uveal melanomas (Onken et al., 2004). Additionally, mutations in BAP1 at 3p21.1 have previously been identified in lung and breast cancer types (Jensen et al., 1998) and have been linked with loss of tumor suppressor function (Ventii et al., 2008). In the current study, BAP1 mutations were identified in 84% of class 2 uveal melanomas but in only one (4%) of the less aggressive class 1-type tumors. Importantly, class 2 tumors display an enhanced risk of metastasis. The correlation between BAP1 mutations and the aggressive phenotype suggests that uveal cells with BAP1 mutations may act as one-hit clones poised to display enhanced metastatic properties following loss of chromosome 3. Interestingly, the BAP1 mutational profile is quite varied and BAP1 mRNA levels are reduced in class 2 tumors even without the presence of BAP1 mutations. Furthermore, BAP1 protein levels were decreased even in tumors with missense point mutations. Together, these findings indicate that multiple mechanisms (mutational, epigenetic and post-translational) are utilized by tumor cells to alter BAP1 levels. As the name suggests, BAP1 was originally identified as a BRCA1-binding protein (Jensen et al., 1998). The gene encodes an ubiquitin C-terminal hydrolase (UCH) subtype of deubiquitinating enzymes, but the specific targets, from which ubiquitin moieties are removed, remain unidentified. Clearly resolving this issue in the context of uveal melanoma will be critical to advancing the field. In a lung cancer cell model, BAP1 functions as a growth suppressor by promoting aberrant accumulation of cells in S phase of the cell cycle and enhancing apoptotic and necrotic forms of cell death in a manner dependent on the critical cysteine within the UCH domain (Ventii et al., 2008). Harbour et al. do not demonstrate that BAP1 re-expression is sufficient to suppress the metastatic potential of uveal melanomas; however, if it does as one would predict from this study, substrates critical in migration, anoikis, and colonization should be considered. Uveal melanomas have a tropism to metastasize to the liver and, thus, whether decreased expression/activity of BAP1 underlies this property should be experimentally tested. Some of the missense point mutations found by Harbour et al. occur at critical sites within the UCH domain and, therefore, are likely to abolish the deubiquitinating activity of BAP1. Other mutations occur within the nuclear localization sequence, BARD1-binding domain and BRCA1-binding domain, but the functional effect of these alterations awaits further investigation. In addition to binding BRCA1, BAP1 forms part of a polycomb repressive complex that may control stem cell pluripotency and histone modifications (Scheuermann et al., 2010). Harbour et al. show that depletion of BAP1 from BAP1 wild-type, class 1 type of uveal melanoma cells alters their morphology and gene expression signature toward a de-differentiated tumor resembling the class 2 type. Thus, whether BAP1 controls a phenotypic switch in uveal melanoma that promotes metastatic potential is an interesting possibility. The identification of BAP1 mutations at high frequency in uveal melanoma represents a significant step forward in this field and will help unravel the complexities of cancer progression in this aggressive tumor type. This study will also raise the spotlight on deubiquitination mechanisms in cancer, which will likely receive attention rivaling that devoted to the opposing force of ubiquitin ligation. Ultimately, it is anticipated that findings from these investigations will lead to the identification of BAP1 substrates and provide new potential drug targets to treat metastatic uveal melanoma.