Deubiquitinases (DUBs) remove ubiquitin groups from lysine residues and thereby typically promote protein stability, whereas DUB inhibitors block these actions of catalytic DUB enzymes and promote the proteasomal degradation of ubiquitinated substrates. Our ongoing studies involve understanding which DUB enzymes can be pharmacologically targeted so as to impair Treg function while maintaining host antitumor immunity. A prime example of success in this approach is that of targeting Usp7, whose inhibition selectively markedly impairs Treg function and thereby limits tumor growth by promoting host effector T cell responses.
Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. Wang L, Kumar S, Dahiya S, Wang F, Wu J, Newick K, Han R, Samanta A, Beier UH, Akimova T, Bhatti TR, Nicholson B, Kodrasov MP, Agarwal S, Sterner DE, Gu W, Weinstock J, Butt TR, Albelda SM, Hancock WW. EBioMedicine. 2016 Nov;13:99-112.
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