Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells

Chen Wang,Chen Wang,Min Xue,Min Xue,Jie Zeng,Jie Zeng,Li-Jie Li,Li-Jie Li,Si-Li He

doi:10.1038/s41419-021-04342-y

Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells

Chen Wang, Chen Wang + Show 7 more

Open Access

https://doi.org/10.1038/s41419-021-04342-y

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Abstract

Cervical cancer is the leading cause of cancer-related deaths in women, and treatment for cervical cancer is very limited. Emerging evidence suggests that targeting ferroptosis is a promising way to treat cancer. Here, we investigated the role of ferroptosis in cervical cancer, with a focus on the Cdc25A/PKM2/ErbB2 axis. Cervical cancer cells were treated with sorafenib to induce ferroptosis. Cellular MDA/ROS/GSH/iron detection assays were used to measure ferroptosis. MTT assays were performed to assess cell viability. qRT-PCR, western blot, and immunostaining assays were performed to measure the levels of proteins. Autophagy was monitored by fluorescence microscopy. Nuclear and cytosolic fractions were isolated to examine the location of PKM2 modifications. Co-IP experiments were conducted to determine the Cdc25A/PKM2 interaction. ChIP assays were performed to measure the binding affinity between H3K9Ac and the ErbB3 promoter, and a dual luciferase assay was performed to examine the transcriptional activity of ErbB2. A nude mouse xenograft model was used to examine the effects of the Cdc25A/ErbB2 axis on tumour growth in vivo. Cdc25A was elevated in human cervical cancer tissues but was reduced during sorafenib-induced ferroptosis of cervical cancer cells. Overexpression of Cdc25A inhibited sorafenib-induced ferroptosis by dephosphorylating nuclear PKM2 and suppressing autophagy. Cdc25A regulated autophagy-induced ferroptosis by increasing ErbB2 levels via the PKM2–pH3T11–H3K9Ac pathway. Cdc25A increased the resistance of cervical cancer to sorafenib, while knockdown of ErbB2 blocked these effects. Cdc25A suppressed autophagy-dependent ferroptosis in cervical cancer cells by upregulating ErbB2 levels through the dephosphorylation of PKM2. These studies revealed that Cdc25A/PKM2/ErbB2 pathway-regulated ferroptosis could serve as a therapeutic target in cervical cancer.

Highlights

Cervical cancer is one of the most common causes of cancerrelated deaths in women, affecting millions of women worldwide [1]
Cdc25A was elevated in human cervical cancer tissues To study the function of Cdc25A in cervical cancer, we first measured its expression level in cervical cancer tissues
By analysing the TCGA dataset, we found that the level of Cdc25A in cervical cancer tissues was much higher than that in normal cervical tissues (Fig. 1A)

Summary

Introduction

Cervical cancer is one of the most common causes of cancerrelated deaths in women, affecting millions of women worldwide [1]. In underdeveloped countries or areas, it is the leading cause of death in women. It is primarily caused by persistent infections of the human papilloma virus (HPV) [2]. The incidence and death rates have dropped due to the increased use of early tests. For patients with regional or distant metastasis, the treatments are limited, and the prognosis remains dismal [3]. It is necessary to explore novel treatments for cervical cancer, which requires a better understanding of the pathogenesis and molecular mechanisms of cancer development and progression

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