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.

De-ubiquitinating enzymes (DUBs) can reverse the modifications catalyzed by ubiquitin ligases and as such are believed to be important regulators of a variety of cellular processes. Several members of this protein family have been associated with human cancers; however, there is little evidence for a direct link between deregulated de-ubiquitination and neoplastic transformation. Ubiquitin C-terminal hydrolase (UCH)-L1 is a DUB of unknown function that is overexpressed in several human cancers, but whether it has oncogenic properties has not been established. To address this issue, we generated mice that overexpress UCH-L1 under the control of a ubiquitous promoter. Here, we show that UCH-L1 transgenic mice are prone to malignancy, primarily lymphomas and lung tumors. Furthermore, UCH-L1 overexpression strongly accelerated lymphomagenesis in Eμ-myc transgenic mice. Aberrantly expressed UCH-L1 boosts signaling through the Akt pathway by downregulating the antagonistic phosphatase PHLPP1, an event that requires its de-ubiquitinase activity. These data provide the first in vivo evidence for DUB-driven oncogenesis and suggest that UCH-L1 hyperactivity deregulates normal Akt signaling.

f Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates processes including mRNA translation, proliferation, and survival. By assembling with different cofactors, mTOR forms two complexes with distinct biological functions. Raptor-bound mTOR (mTORC1) governs cap-dependent mRNA translation, whereas mTOR, rictor, and mSin1 (mTORC2) activate the survival and proliferative kinase Akt. How the balance between the competing needs for mTORC1 and -2 is controlled in normal cells and deregulated in disease is poorly understood. Here, we show that the ubiquitin hydrolase UCH-L1 regulates the balance of mTOR signaling by disrupting mTORC1. We find that UCH-L1 impairs mTORC1 activity toward S6 kinase and 4EBP1 while increasing mTORC2 activity toward Akt. These effects are directly attributable to a dramatic rearrangement in mTOR complex assembly. UCH-L1 disrupts a complex between the DDB1-CUL4 ubiquitin ligase complex and raptor and counteracts DDB1-CUL4-mediated raptor ubiquitination. These events lead to mTORC1 dissolution and a secondary increase in mTORC2. Experiments in Uchl1-deficient and transgenic mice suggest that the balance between these pathways is important for preventing neurodegeneration and the development of malignancy. These data establish UCH-L1 as a key regulator of the dichotomy between mTORC1 and mTORC2 signaling.

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