Abstract
Dysregulation of components of the ubiqutin system has been linked to many diseases including melanoma. This is vital since the post-translational modification of different proteins via direct ubiquitin attachment is an important process for various cellular processes. CYLD is a tumor suppressor gene and deubiquitinating enzyme, which can remove polyubiquitin chains from their specific substrate and interfere with different signaling pathways. CYLD is frequently downregulated or even lost in melanoma cell lines or tissues compared to melanocytes. Down-regulation of CYLD leads to sustained oncogenic signaling that promotes melanoma progression and metastasis. In this review, we summarize the recent insights into the mechanisms which are responsible for the down-regulation of CYLD levels in melanoma and the signaling interactions of the CYLD gene product in melanoma. We argue that these recent insights into CYLD function invite the development of novel molecular strategies for melanoma prevention and treatment.
Highlights
Melanoma is the most aggressive skin cancer, with an incidence that continues to rise
We summarize the recent insights into the mechanisms which are responsible for the down-regulation of cylindromatosis gene (CYLD) levels in melanoma and the signaling interactions of the CYLD gene product in melanoma
We argue that these recent insights into CYLD function invite the development of novel molecular strategies for melanoma prevention and treatment
Summary
Melanoma is the most aggressive skin cancer, with an incidence that continues to rise. The ubiquitination process is counter-regulated by a family of deubiquitinases (DUBs) [3] These enzymes can cleave ubiquitin from ubiquitin-conjugated protein substrates, ubiquitin precursors, ubiquitin adducts, and polyubiquitin [4]. The human genome encodes approximately 90 putative DUBs and analysis of alterations in DUB expression in melanoma by in situ hybridization on tissue microarrays identified five genes (USP10, USP11, USP22, USP48 and COPS5) that were significantly over-expressed, compared with benign nevi [5] Out of these five genes, the expression of USP10, USP11 and USP22 was significantly higher in metastatic melanoma compared with benign nevi, and in primitive tumors, it was suggested that their expression is associated with a more aggressive and invasive phenotype [5]. This review will confine itself to discussing the tumor suppressor function of CYLD in melanoma
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