Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
Yu‐Shui Ma, Xiaofeng Wang, Yunjie Zhang, Pei Luo, Hui-Deng Long, Liu Li, Huiqiong Yang, Ruting Xie, Chengyou Jia, Gai‐Xia Lu, Zhengyan Chang, Jiajia Zhang, Shaobo Xue, Zhongwei Lv, Fei Yu, Qing Xia, Da Fu
Abstract
Functional elimination of p53 is a common feature of a large percentage of human malignancies. Here, we report the development of a pharmacological strategy aimed at restoring p53 function and its use for targeted therapy in p53-deficient mice. Specific inhibition of deubiquitinases ubiquitin-specific peptidase 14 (USP14) resulted in durable tumor regressions of autochthonous lymphomas and sarcomas in p53-deficient mice without affecting normal tissues, and therapeutic response was correlated with an increase in the ubiquitination of constitutive photomorphogenesis 9 (COP9) signalosome subunit 5 (COPS5), a key negative regulatory effector for p53. Inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and a p53-dependent and -independent regulation mechanism by USP14. This series highlights the utility of proteasome deubiquitinating activity inhibition as a novel treatment paradigm for p53-deficient cancers. In addition, it provides preliminary evidence that inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and p53-dependent and -independent regulation mechanism by USP14. These findings suggest that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target for patients with p53 deficiency.