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

Author

Listed:
  • Xiao Gao

    (East China Normal University
    The Second Military Medical University
    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
    The Second Military Medical 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
    The Second Military Medical 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
    Dan L. Duncan Cancer Center, Baylor College of Medicine)

  • Lei Li

    (East China Normal University)

  • Jianru Xiao

    (East China Normal University
    The Second Military Medical University)

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.

Suggested Citation

  • 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, 2020. "The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17667-7
    DOI: 10.1038/s41467-020-17667-7
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