Targeting 19S-Proteasome Deubiquitinase Rpn11/POH1/PSMD14 in Multiple Myeloma

IntroductionDeregulation of the ubiquitin-proteasome system (UPS) is linked to pathogenesis of various human diseases, including cancer. Targeting the proteasome is an effective therapy in multiple myeloma (MM) patients. Recent research efforts led to the discovery of newer agents that target enzymes modulating protein ubiquitin-conjugation/deconjugation rather than the proteasome itself, with the goal of generating more specific and less toxic antitumor therapies. Ubiquitylation is a dynamic reversible process coordinated by many enzymes: ubiquitin ligases attach ubiquitin to proteins allowing for their degradation, whereas deubiquitylating (DUB) enzymes deconjugate ubiquitin from target proteins, thereby preventing their proteasome-mediated degradation. Rpn11 is a DUB enzyme associated with the 19S regulatory particle lid of the proteasome that removes ubiquitin from target proteins to facilitate protein degradation by 20S proteasome core particle. Here we examined the role of Rpn11 in MM using both biochemical and RNA interference strategies.