Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines

Yulin Zhang,Bin Huang,Tobias Wikerholmen,Xingang Li,Junpeng Wang,Kaiyan Xi,Frits Thorsen,Zichao Feng,Yuan Ma,Zhong Yao,Yaotian Hu,Zhimin Zhao,Yang Kong,Shilei Ni,Jian Wang,Mingzhi Han,Anjing Chen,Feihu Zhao

doi:10.1038/s41388-020-01622-3

Yulin Zhang, Bin Huang + Show 16 more

Open Access

https://doi.org/10.1038/s41388-020-01622-3

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Abstract

Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P < 0.001). Protein levels of COPZ1 were significantly increased in GBM compared to non-neoplastic brain tissue samples in immunohistochemistry and western blot analysis. SiRNA knockdown of COPZ1 suppressed proliferation of U87MG, U251 and P3#GBM in vitro. Stable expression of a COPZ1 shRNA construct in U87MG inhibited tumor growth in vivo by ~60% relative to controls at day 21 after implantation (P < 0.001). Kaplan–Meier analysis of the survival data demonstrated that the overall survival of tumor bearing animals increased from 20.8 days (control) to 27.8 days (knockdown, P < 0.05). COPZ1 knockdown also led to the increase in nuclear receptor coactivator 4 (NCOA4), resulting in the degradation of ferritin, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. These data demonstrate that COPZ1 is a critical mediator in iron metabolism. The COPZ1/NCOA4/FTH1 axis is therefore a novel therapeutic target for the treatment of human GBM.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with an annual incidence of 5.26 per 100,000 population [1, 2]
The results showed that complex subunit zeta 1 (COPZ1) expression was positively associated with tumor grade and liquefactive necrosis, independent from age, gender, tumor size, and edema, which suggested that COPZ1 could be a potential diagnostic marker for glioma patients (Table 1, p < 0.05)
Since COPZ1 is involved in iron metabolism [27, 30], we studied whether knockdown of COPZ1 induced ferroptosis in GBM cells

Summary

Introduction

Prognosis and the quality of life of GBM patients are poor [3]. GBM cells have altered expression of many iron metabolism-related proteins and iron-related enzyme activities [5]. These changes often contribute to the relatively high availability of iron in GBM cells and promote the function of iron-dependent proteins that are involved in many physiological processes, such as tumor initiation, progression, and metastasis [6,7,8]. An understanding of the molecular mechanisms involved in the process in GBM will help to exploit ferroptosis in the treatment of the disease

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