ZMIZ2 promotes the development of triple-receptor negative breast cancer

Xiaopan Zou,Wei Wei,Jiang Li,Yan Liu,Nobumoto Watanabe,Jun Di,Xiaomeng Li

doi:10.1186/s12935-021-02393-x

Abstract

BackgroundTriple-receptor negative breast cancer (TNBC) is an aggressive breast tumor subtype that generally has a poor prognosis. This study aimed to investigate the role and regulatory mechanisms of Zinc finger MIZ-type containing 2 (ZMIZ2) in relation to TNBC.MethodsBased on data from The Cancer Genome Atlas (TCGA), the expression of ZMIZ2 in different subtypes and its correlation with androgen receptor (AR) were analyzed, and a regulatory mechanism network was constructed. The expression and prognostic value of ZMIZ2 in clinical TNBC tissue samples were also investigated. Furthermore, in vitro studies were conducted to investigate the effects of ZMIZ2 knockdown on the malignant behaviors of TNBC cells and target gene expression.ResultsBased on TCGA data, ZMIZ2 was found to be significantly upregulated in TNBC tissues and its expression was negatively correlated with AR expression. Key relationships, such as the ZMIZ2-CCL5, ZMIZ2/AR-MCM3, ZMIZ2/AR-E2F4, and the ZMIZ2/AR-DHX38 were identified, which were enriched in NOD-like receptor signaling pathway/toll-like receptor signaling pathway, DNA replication, cell cycle, and spliceosome, respectively. Moreover, ZMIZ2 was upregulated in clinical breast cancer tissues and its high expression was correlated with the poor prognosis of TNBC patients. Furthermore, ZMIZ2 expression was increased in breast cancer cells, and a knockdown of ZMIZ2 inhibited MDA-MB-231 cell proliferation, migration, and invasion, induced cell cycle arrest in the G1 phase, and promoted cell apoptosis. Furthermore, ZMIZ2 knockdown inhibited the mRNA and protein expression of CCL5, MCM3, E2F4, and DHX38.ConclusionOur findings reveal that ZMIZ2 is upregulated in TNBC tissues and is associated with its poor prognosis. ZMIZ2 may promote TNBC progression by promoting the expression of its target genes and affecting the corresponding pathways. Consequently, ZMIZ2 may serve as a promising target for future TNBC treatments.

Highlights

Triple-receptor negative breast cancer (TNBC) is an aggressive breast tumor subtype that generally has a poor prognosis
In vitro validation of the Zinc finger MIZ-type containing 2 (ZMIZ2) expression in breast cancer cell lines and the oncogenic role of ZMIZ2 in TNBC cells ZMIZ2 expression was increased in breast cancer cells The expression levels of ZMIZ2 were assessed in the three breast cancer cell lines and the breast epithelial cells
In vitro experiments revealed that ZMIZ2 expression was increased in breast cancer cells, and the knockdown of ZMIZ2 inhibited MDAMB-231 cell proliferation, migration, and invasion, induced cell cycle arrest in G1 phase, and promoted cell apoptosis

Summary

Introduction

Triple-receptor negative breast cancer (TNBC) is an aggressive breast tumor subtype that generally has a poor prognosis. This study aimed to investigate the role and regulatory mechanisms of Zinc finger MIZ-type containing 2 (ZMIZ2) in relation to TNBC. Zinc finger MIZ-type containing 2 (ZMIZ2), named ZIMP7, is a protein inhibitor of activated STAT (PIAS)-like protein and a transcriptional coactivator [6]. AR has been suggested to play a critical role in male sexual development, as well as in the growth and survival of normal and malignant prostate cells [6]. ZMIZ2 is highly expressed in the testis and promotes the growth of prostate cancer cells [6]. AR seems to play an important role in the carcinogenesis of TNBC, as it is reportedly expressed in 10–50% of TNBC cases [9], and those with an the AR-positive subtype are susceptible to AR blockades [9,10,11]. Given the regulatory relationship between ZMIZ2 and AR, as well as the role of AR in TNBC, we hypothesize that ZMIZ2 plays a key role in the carcinogenesis of TNBC, and may serve as a novel biomarker for TNBC

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