Deubiquitinating enzymes (DUBs) as potential therapeutic targets for cancer treatment.

Approval of the proteasome inhibitor bortezomib (a.k.a. Velcade) for treatment of multiple myeloma has focused attention on the ubiquitin-proteasome pathway as a suitable target for cancer treatment. DUBs are recognized as particularly “druggable targets” in the pathway, with many groups developing inhibitors as potential anti-cancer agents. Dr. Joan Seoane at the Vall d’Hebron Institute of Oncology in Barcelona, Spain and international colleagues demonstrated that the DUB, ubiquitin-specific peptidase 15 (USP15), serves as an important regulator of transforming growth factor β (TGF-β) in glioblastoma and other malignancies (Eichhorn et al (2012) Nat Med, doi: 10.1038/nm.2619). TGF-β functions as an oncogenic factor in advanced tumors that activates a heterodimeric complex formed by type I and II TGF-β receptors (TβR-I and TβR-II) to initiate a signaling cascade. The pathway is controlled through ubiquitination, and reversed by USP15. Inhibiting USP15 in a mouse model of human glioblastoma diminishes TGF-β activity, leading to the development of smaller tumors. A number of human glioblastoma tumors display USP15 gene amplification, which is associated with particularly poor patient prognosis.

Enzo Life Sciences offers comprehensive tools for examining the crucial regulatory roles that DUBs may play as potential drug candidates for therapeutic intervention.

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