NUSAP1 potentiates chemoresistance in glioblastoma through its SAP domain to stabilize ATR

Yuzu Zhao,Jiang He,Hongjuan Cui,Yongsen Li,Shengqing Lv

doi:10.1038/s41392-020-0137-7

Abstract

NUSAP1, which is a microtubule-associated protein involved in mitosis, plays essential roles in diverse biological processes, especially in cancer biology. In this study, NUSAP1 was found to be overexpressed in GBM tissues in a grade-dependent manner compared with normal brain tissues. NUSAP1 was also highly expressed in GBM patients, dead patients, and GBM cells. In addition, NUSAP1 was found to participate in cell proliferation, apoptosis, and DNA damage in GBM cells. Ataxia telangiectasia and Rad3-related protein (ATR) are a primary sensor of DNA damage, and ATR is also a promising target in cancer therapy. Here, we found that NUSAP1 positively regulated the expression of ATR. Mechanistically, NUSAP1 suppressed the ubiquitin-dependent proteolysis of ATR. The SAP (SAF-A/B, Acinus, and PIAS) domain is a common motif of many SUMO (small ubiquitin-like modifier) E3 ligases, and this domain is involved in substrate recognition and ligase activity. This study further demonstrated that the SAP domain of NUSAP1 promoted the sumoylation of ATR, and thereby antagonized the ubiquitination of ATR. These results suggest that NUSAP1 stabilizes ATR by sumoylation. Moreover, NUSAP1 potentiated chemotherapeutic resistance to temozolomide (TMZ) and doxorubicin (DOX) through its SAP domain. Overall, this study indicates that NUSAP1 is a promising therapeutic target in GBM.

Highlights

Glioblastoma multiforme (GBM), called grade IV astrocytoma, along with other gliomas, constitutes the vast majority of malignant brain tumors.[1,2] GBM is the most aggressive brain tumor with high mortality, poor prognosis, and short survival.[3]
This study indicates that Nucleolar and spindle-associated protein 1 (NUSAP1) acts as a tumor-related gene in GBM, and that NUSAP1 inhibits cell proliferation and induces apoptosis and DNA damage in GBM
NUSAP1 is highly expressed in GBM patients as well as in GBM cells To investigate the role of NUSAP1 in GBM, an immunochemistry (IHC) assay was performed to detect the expression of NUSAP1 in 72 normal brain and glioma samples

Summary

Introduction

Glioblastoma multiforme (GBM), called grade IV astrocytoma, along with other gliomas, constitutes the vast majority of malignant brain tumors.[1,2] GBM is the most aggressive brain tumor with high mortality, poor prognosis, and short survival.[3]. Genes involved in DNA damage processing are targets for tumor therapy.[7,8,9,10] Ataxia telangiectasia mutated (ATM)

Methods

Results

Conclusion