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 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; Jianru Xiao

doi:10.1038/s41467-020-17667-7

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 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^*, Jianru Xiao^*

^*Corresponding author for this work

School of Life Sciences

East China Normal University
Changzheng Hospital
Ohio State University
Hangzhou Normal University
Guangdong Second Provincial General Hospital
National Institutes of Health
Peking University
University of California at Irvine
The Second Chengdu Municipal Hospital
Shanghai Jiao Tong University
Baylor College of Medicine
University of Haifa

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 language	English
Article number	3904
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17667-7
State	Published - 1 Dec 2020

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SDG 3 Good Health and Well-being

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10.1038/s41467-020-17667-7

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Gao, X., Wang, Q., Wang, Y., Liu, J., Liu, S., Liu, J., Zhou, X., Zhou, L., Chen, H., Pan, L., Chen, J., Wang, D., Zhang, Q., Shen, S., Xiao, Y., Wu, Z., Cheng, Y., Chen, G., Krubra, S., ... Xiao, J. (2020). The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells. Nature Communications, 11(1), Article 3904. https://doi.org/10.1038/s41467-020-17667-7

@article{dc37d894d77a4ccb90a49fa9d26e1da2,

title = "The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells",

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.",

author = "Xiao Gao and Qingwei Wang and Ying Wang and Jiang Liu and Shuang Liu and Jian Liu and Xingli Zhou and Li Zhou and Hui Chen and Linian Pan and Jiwei Chen and Da Wang and Qing Zhang and Shihui Shen and Yu Xiao and Zhipeng Wu and Yiyun Cheng and Geng Chen and Syeda Krubra and Jun Qin and Lan Huang and Pei Zhang and Chuangui Wang and Moses, \{Robb E.\} and Lonard, \{David M.\} and Malley, \{Bert W.O{\textquoteright}\} and Fuad Fares and Bianhong Zhang and Xiaotao Li and Lei Li and Jianru Xiao",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-17667-7",

language = "英语",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Gao, X, Wang, Q, Wang, Y, Liu, J, Liu, S, Liu, J, Zhou, X, Zhou, L, Chen, H, Pan, L, Chen, J, Wang, D, Zhang, Q, Shen, S, Xiao, Y, Wu, Z, Cheng, Y, Chen, G, Krubra, S, Qin, J, Huang, L, Zhang, P, Wang, C, Moses, RE, Lonard, DM, Malley, BWO, Fares, F, Zhang, B, Li, X, Li, L & Xiao, J 2020, 'The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells', Nature Communications, vol. 11, no. 1, 3904. https://doi.org/10.1038/s41467-020-17667-7

TY - JOUR

T1 - The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells

AU - Gao, Xiao

AU - Wang, Qingwei

AU - Wang, Ying

AU - Liu, Jiang

AU - Liu, Shuang

AU - Liu, Jian

AU - Zhou, Xingli

AU - Zhou, Li

AU - Chen, Hui

AU - Pan, Linian

AU - Chen, Jiwei

AU - Wang, Da

AU - Zhang, Qing

AU - Shen, Shihui

AU - Xiao, Yu

AU - Wu, Zhipeng

AU - Cheng, Yiyun

AU - Chen, Geng

AU - Krubra, Syeda

AU - Qin, Jun

AU - Huang, Lan

AU - Zhang, Pei

AU - Wang, Chuangui

AU - Moses, Robb E.

AU - Lonard, David M.

AU - Malley, Bert W.O’

AU - Fares, Fuad

AU - Zhang, Bianhong

AU - Li, Xiaotao

AU - Li, Lei

AU - Xiao, Jianru

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85089133889

U2 - 10.1038/s41467-020-17667-7

DO - 10.1038/s41467-020-17667-7

M3 - 文章

C2 - 32764536

AN - SCOPUS:85089133889

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3904

ER -

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

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