DUBs and cancer The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors

It is increasingly apparent that ubiquitin (Ub) mediated events are critical in cell proliferation. With much attention placed on the ubiquitin-proteasome pathway as a target for pharmacologic intervention, we must consider the role of deubiquitinating enzymes (DUBs) as regulators of these processes. There is a growing recognition of DUBs that are mutated in human cancers suggesting their roles as oncogenes and tumor suppressors. There is also an expanding list of enzymes that play essential roles in pathways that contribute to, or support cellular adaptations required for, malignant transformation (non-oncogenes). (Luo J, Cell 2009) Here we review the association of DUBs with cancer beginning with those with known mutations in human disease and concluding with those with a clear role in regulating cancer-relevant pathways. The molecular mechanisms underlying the association with cancer are described along with data regarding altered expression in human diseases. Although few specific, cell permeable, inhibitors exist, DUBs as a class are eminently drugable targets making it important to better understand the sites at which such modulation may have useful effects therapeutically. Given the numbers of ubiquitin-dependent pathways where we do not yet understand the role of deubiquitination, it is certain that the list of cancer-related DUBs will grow in coming years.