The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells

Xiao Gao, Qingwei Wang, Ying Wang, Jiang Liu, Shuang Liu, Jian Liu, Xingli Zhou, Li Zhou, Hui Chen, Linian Pan, Jiwei Chen, Da Wang, Qing Zhang, Shihui Shen, Yu Xiao, Zhipeng Wu, Yiyun Cheng, Geng Chen, Syeda Kubra, Jun Qin, Lan Huang, Pei Zhang, Chuangui Wang, Robb E. Moses, David M. Lonard, Bert W. O’ Malley, Fuad Fares, Bianhong Zhang (), Xiaotao Li (), Lei Li () and Jianru Xiao ()
Additional contact information
Xiao Gao: East China Normal University
Qingwei Wang: The Ohio State University
Ying Wang: Hangzhou Normal University
Jiang Liu: Hangzhou Normal University
Shuang Liu: Guangdong Second Provincial General Hospital
Jian Liu: National Institute of Environmental Health Sciences (NIEHS)
Xingli Zhou: East China Normal University
Li Zhou: East China Normal University
Hui Chen: East China Normal University
Linian Pan: East China Normal University
Jiwei Chen: East China Normal University
Da Wang: East China Normal University
Qing Zhang: Guangdong Second Provincial General Hospital
Shihui Shen: East China Normal University
Yu Xiao: East China Normal University
Zhipeng Wu: East China Normal University
Yiyun Cheng: East China Normal University
Geng Chen: East China Normal University
Syeda Kubra: East China Normal University
Jun Qin: National Center for Protein Sciences (Beijing) and Peking University Cancer Hospital, State Key Laboratory of Proteomics, Institute of Lifeomics
Lan Huang: University of California
Pei Zhang: The Second Chengdu Municipal Hospital
Chuangui Wang: Shanghai Jiao Tong University School of Medicine
Robb E. Moses: Dan L. Duncan Cancer Center, Baylor College of Medicine
David M. Lonard: Dan L. Duncan Cancer Center, Baylor College of Medicine
Bert W. O’ Malley: Dan L. Duncan Cancer Center, Baylor College of Medicine
Fuad Fares: University of Haifa
Bianhong Zhang: East China Normal University
Xiaotao Li: East China Normal University
Lei Li: East China Normal University
Jianru Xiao: East China Normal University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53−/− and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.

Date: 2020
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DOI: 10.1038/s41467-020-17667-7

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