The REG\u03b3 inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells

Xiao Gao ,Linian Pan,Hui Chen ,Shuang Liu,Geng Chen,Li Zhou,Ying Wang,Jun Qin,Da Wang ,David M Lonard,Pei Zhang,Syeda Kubra,Robb E Moses,Qingwei Wang,Xiaotao Li,Xinran Zhou ,Jiang Liu,Shihui Shen,Jiwei Chen,Chuangui Wang,Yiyun Cheng ,Lan Huang,Yu Xiao,Fuad Fares,Lei Li,Qing Zhang ,Bert W O’ Malley ,Jian Liu,Zhipeng Wu,Bianhong Zhang,Jianru Xiao

doi:10.1038/s41467-020-17667-7

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.

Highlights

A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53
UV-induced stabilization of p21 was observed in both WT and p53−/− skin, but no differences in p21 were noted before or after UV treatment for REGγ−/− and p53−/−/REGγ−/− double-knockout mice (Fig. 5f). These results suggest that the CDC25A–NIP30-REGγ pathway is important in p53-independent regulation of p21 following DNA damage in vitro and in vivo
We propose a model in which accumulation or degradation of CDC25A during the cell cycle or after DNA damage leads to regulation of REGγ via NIP30, controlling p21 levels in a p53independent manner (Fig. 6e)

Summary

Introduction

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. 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. Key transitions in the cell cycle are regulated by a family of serine/threonine protein kinases termed cyclin-dependent kinases (CDKs). Whether p21 can be degraded during a specific stage of the cell cycle by the ubiquitinindependent proteasome pathway is still under debate. The removal of inhibitory phosphorylation on CDK proteins by dual-specificity phosphatases of the CDC25 family is a crucial step in the activation of CDK-cyclin complexes. CDC25A is a short-lived protein that is degraded in response to DNA damage[24]; phosphorylation of CDC25A triggers ubiquitin-mediated degradation of checkpoint kinases in response to UV exposure[25,26]. Checkpoint kinase 1 (Chk1) and serine–threonine kinase[38] (STK) can phosphorylate

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Conclusion