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EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers.

ABSTRACT: Triple-negative breast cancer (TNBC) is characterized by low expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), which is the most aggressive subtype with poor outcome among breast cancers. The underlying mechanisms of TNBC remain unclear and there is a lack of biomarkers. In this study we conducted an in silico assay and found that FOXC1 was highly expressed in ER^-/PR^-/HER2^- breast cancers, which was confirmed by qRT-PCR, immunohistochemistry, and Western blot analysis. FOXC1 was more highly expressed in TNBCs than the other breast cancers. Kaplan-Meier plotter revealed that expression of FOXC1 was associated with overall survival (OS) of patients with breast cancers. Expression of FOXC1 was reversely associated with level of H3K27me3, which was methylated by EZH2. In MCF-7 and T47D cells, inhibition of EZH2 by DZNeP or GSK343 concentration- and time-dependently increased expression of FOXC1. Finally, we demonstrated that the expression of FOXC1 was associated with resistance of doxorubicin treatment of breast cancer cells. In conclusion, these results suggest that FOXC1 may be a potential biomarker or drug target for TNBCs, and that downregulation of FOXC1 could have therapeutic value in treatment of TNBCs.

SUBMITTER: Zheng XJ

PROVIDER: S-EPMC8209002 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers.

Zheng Xiang-Jin XJ Li Wan W Yi Jie J Liu Jin-Yi JY Ren Li-Wen LW Zhu Xiao-Ming XM Liu Shi-Wei SW Wang Jin-Hua JH Du Guan-Hua GH

Acta pharmacologica Sinica 20201014 7

Triple-negative breast cancer (TNBC) is characterized by low expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), which is the most aggressive subtype with poor outcome among breast cancers. The underlying mechanisms of TNBC remain unclear and there is a lack of biomarkers. In this study we conducted an in silico assay and found that FOXC1 was highly expressed in ER-/PR-/HER2- breast cancers, which ...[more]

PMID: 33057161

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Project description:ObjectivesAbdominal aortic aneurysm (AAA) has a high risk of rupture of the aorta and is one of the leading causes of death in older adults. This study is aimed at confirming the influence and mechanism of the abnormally expressed ANXA6 gene in AAA.MethodsClinical samples were collected for proteome sequencing to screen for differentially expressed proteins. An Ang II-induced vascular smooth muscle cell (VSMC) aging model as well as an AAA animal model was used. Using RT-qPCR to detect the mRNA levels of EZH2, ANXA6, IK-6, and IL-8 in cells and tissues were assessed. Western blotting and immunohistochemistry staining were used apply for the expression of associated proteins in cells and tissues. SA-β-gal staining, flow cytometry, and DHE staining were used to detect senescent cells and the level of ROS. The cell cycle was assessed by flow cytometry. Arterial pathology was observed by HE staining. The aging of VSMCs in arterial tissue was assessed by coimmunofluorescence for α-SMA and p53.ResultsThere were 24 differentially expressed proteins in the AAA clinical samples, including 10 upregulated protein and 14 downregulated protein, and the differential expression of ANXA6 was associated with vascular disease. Our study found that ANXA6 was highly expressed and EZH2 was lowly expressed in an Ang II-induced VSMC aging model. Knockdown of ANXA6 or overexpression of EZH2 inhibited Ang II-induced ROS, inhibited cell senescence, decreased Ang II evoked G1 arrest, and increased cells in G2 phase, while overexpression of ANXA6 played the opposite role. Overexpression of EZH2 inhibited ANXA6 expression by increasing H3K27me3 modification at the ANXA6 promoter. Simultaneous overexpression of EZH2 and the protective effect of EZH2 on cell senescence were partially reversed by ANXA6. Similarly, ANXA6 was highly expressed and EZH2 was lowly expressed in an Ang II-induced AAA animal model. Knockdown of ANXA6 and overexpression of EZH2 alleviated Ang II-induced VSMC senescence and inhibited AAA progression, while simultaneous overexpression of EZH2 and ANXA6 partially reversed the protective effect of EZH2 on AAA.ConclusionEZH2 regulates the ANXA6 promoter H3K27me3 modification, inhibits ANXA6 expression, alleviates Ang II-induced VSMC senescence, and inhibits AAA progression.

Dataset Information

EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers.

Publications

EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers.

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