Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency

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-specif...

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Main Authors:	Yu-Shui Ma, Xiao-Feng Wang, Yun-Jie Zhang, Pei Luo, Hui-Deng Long, Liu Li, Hui-Qiong Yang, Ru-Ting Xie, Cheng-You Jia, Gai-Xia Lu, Zheng-Yan Chang, Jia-Jia Zhang, Shao-Bo Xue, Zhong-Wei Lv, Fei Yu, Qing Xia, Da Fu
Format:	Article
Language:	English
Published:	Elsevier 2020-03-01
Series:	Molecular Therapy: Oncolytics
Online Access:	http://www.sciencedirect.com/science/article/pii/S237277052030005X

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collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Yu-Shui Ma Xiao-Feng Wang Yun-Jie Zhang Pei Luo Hui-Deng Long Liu Li Hui-Qiong Yang Ru-Ting Xie Cheng-You Jia Gai-Xia Lu Zheng-Yan Chang Jia-Jia Zhang Shao-Bo Xue Zhong-Wei Lv Fei Yu Qing Xia Da Fu
spellingShingle	Yu-Shui Ma Xiao-Feng Wang Yun-Jie Zhang Pei Luo Hui-Deng Long Liu Li Hui-Qiong Yang Ru-Ting Xie Cheng-You Jia Gai-Xia Lu Zheng-Yan Chang Jia-Jia Zhang Shao-Bo Xue Zhong-Wei Lv Fei Yu Qing Xia Da Fu Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency Molecular Therapy: Oncolytics
author_facet	Yu-Shui Ma Xiao-Feng Wang Yun-Jie Zhang Pei Luo Hui-Deng Long Liu Li Hui-Qiong Yang Ru-Ting Xie Cheng-You Jia Gai-Xia Lu Zheng-Yan Chang Jia-Jia Zhang Shao-Bo Xue Zhong-Wei Lv Fei Yu Qing Xia Da Fu
author_sort	Yu-Shui Ma
title	Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
title_short	Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
title_full	Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
title_fullStr	Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
title_full_unstemmed	Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency
title_sort	inhibition of usp14 deubiquitinating activity as a potential therapy for tumors with p53 deficiency
publisher	Elsevier
series	Molecular Therapy: Oncolytics
issn	2372-7705
publishDate	2020-03-01
description	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. Keywords: p53, COPS5, USP14, DUB, ubiquitination
url	http://www.sciencedirect.com/science/article/pii/S237277052030005X
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spelling	doaj-19e5d6bc50b64885983f3238c6b01f1b2020-11-25T01:45:13ZengElsevierMolecular Therapy: Oncolytics2372-77052020-03-0116147157Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 DeficiencyYu-Shui Ma0Xiao-Feng Wang1Yun-Jie Zhang2Pei Luo3Hui-Deng Long4Liu Li5Hui-Qiong Yang6Ru-Ting Xie7Cheng-You Jia8Gai-Xia Lu9Zheng-Yan Chang10Jia-Jia Zhang11Shao-Bo Xue12Zhong-Wei Lv13Fei Yu14Qing Xia15Da Fu16Central Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaDepartment of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, ChinaDepartment of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaCentral Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China; Corresponding author: Da Fu, Central Laboratory for Medical Research, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Middle 301 Yanchang Road, Shanghai 200072, China.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. Keywords: p53, COPS5, USP14, DUB, ubiquitinationhttp://www.sciencedirect.com/science/article/pii/S237277052030005X

Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency

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