Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT

Qing Li,Dong Wang,Meng-Sheng Deng,Cheng-Yuan Qian,Wei Duan,Guanbin Song,Zhi-Wei Zhou,Jian-Min Wang,Kenneth D Westover,Cheng-Yi Mao,Cheng-Xiong Xu,Shu-Nan Wang,Dan Zi

doi:10.1186/s13046-021-02006-5

Abstract

BackgroundMetastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied.MethodsWe used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models.ResultsClinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT.ConclusionOur findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.

Highlights

Metastasis is a major challenge in cervical cancer treatment
Wei et al reported that upregulated apyrimidinic endonuclease 1 (APE1) was closely associated with lymph node metastasis in gastric cancer [22]. These findings suggest that APE1 may be involved in the regulation of E-cadherin-mediated epithelialmesenchymal transition (EMT) and tumor metastasis, but the mechanism is unclear
High expression of APE1 is closely associated with EMT and lymph node metastasis in cervical cancer patients To investigate whether the high expression of APE1 in cervical cancer is related to EMT and metastasis, we performed gene set enrichment analysis (GSEA) using transcriptome data from four cervical cancer samples expressing high levels of APE1 and four cervical cancer samples expressing low levels of APE1 (Fig. 1a and Fig. S2)

Summary

Introduction

Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. The biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. The major challenge in cervical cancer treatment is metastasis because most of the mortality associated with cervical cancer is caused by metastasis [3]. The clinical data show that EMT is closely related to a poor prognosis in cervical cancer patients [9, 10]. Clinical data show that low expression of E-cadherin is closely associated with metastasis and a poor prognosis in cervical cancer patients [15, 16]

Methods

Results

Discussion

Conclusion