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Open Access 01-12-2019 | Breast Cancer | Research

Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells

Authors: Lufeng Zheng, Qianqian Guo, Chenxi Xiang, Shijia Liu, Yuzhang Jiang, Lanlan Gao, Haiwei Ni, Ting Wang, Qiong Zhao, Hai Liu, Yingying Xing, Yaohui Wang, Xiaoman Li, Tao Xi

Published in: Journal of Hematology & Oncology | Issue 1/2019

Abstract

Background

The expression of CYP4Z1 and the pseudogene CYP4Z2P has been shown to be specifically increased in breast cancer by our group and others. Additionally, we previously revealed the roles of the competitive endogenous RNA (ceRNA) network mediated by these genes (ceRNET_CC) in breast cancer angiogenesis, apoptosis, and tamoxifen resistance. However, the roles of ceRNET_CC in regulating the stemness of breast cancer cells and the mechanisms through which ceRNET_CC is regulated remain unclear.

Methods

Transcriptional factor six2, CYP4Z1-3′UTR, and CYP4Z2P-3′UTR were stably overexpressed or knocked down in breast cancer cells via lentivirus infection. ChIP-sequencing and RNA-sequencing analysis were performed to reveal the mechanism through which ceRNET_CC is regulated and the transcriptome change mediated by ceRNET_CC. Clinical samples were used to validate the correlation between six2 and ceRNET_CC. Finally, the effects of the six2/ceRNET_CC axis on the stemness of breast cancer cells and chemotherapy sensitivity were evaluated by in vitro and in vivo experiments.

Results

We revealed that ceRNET_CC promoted the stemness of breast cancer cells. Mechanistically, six2 activated ceRNET_CC by directly binding to their promoters, thus activating the downstream PI3K/Akt and ERK1/2 pathways. Finally, we demonstrated that the six2/ceRNET_CC axis was involved in chemoresistance.

Conclusions

Our results uncover the mechanism through which ceRNET_CC is regulated, identify novel roles for the six2/ceRNET_CC axis in regulating the stemness of breast cancer cells, and propose the possibility of targeting the six2/ceRNET_CC axis to inhibit breast cancer stem cell (CSC) traits.

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Title: Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells
Authors: Lufeng Zheng
Qianqian Guo
Chenxi Xiang
Shijia Liu
Yuzhang Jiang
Lanlan Gao
Haiwei Ni
Ting Wang
Qiong Zhao
Hai Liu
Yingying Xing
Yaohui Wang
Xiaoman Li
Tao Xi
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Published in: Journal of Hematology & Oncology / Issue 1/2019
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-019-0697-6

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