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 Krubra, Jun QinLan Huang, Pei Zhang, Chuangui Wang, Robb E. Moses, David M. Lonard, Bert W.O’ Malley, Fuad Fares, Bianhong Zhang, Xiaotao Li, Lei Li, Jianru Xiao

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3904
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

Bibliographical note

Funding Information:
This work was supported by the National Natural Science Foundation of China (31670882, 31730017, 81672883, 81903244), the Science and Technology Commission of Shanghai Municipality (16ZR1410000, 16QA1401500), and National Institutes of Health grant R01GM074830 to L.H. The Foundation of Guangdong Second Provincial General Hospital (2017-001) and Doctoral workstation foundation of Guangdong Second Provincial General hospital (2019BSGZ008) and Guangzhou Science and Technology Plan Project (202002030404) to LS. We thank ECNU public platform for innovation (011) for mouse facility work. We apprecite Dr. Yongyan Dang for helpful suggestions.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)

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