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Exp Cell Res. 2017 Oct 15;359(2):405-414. doi: 10.1016/j.yexcr.2017.08.024. Epub 2017 Aug 18.

GSKJ4, an H3K27me3 demethylase inhibitor, effectively suppresses the breast cancer stem cells.

Author information

1
Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou 215021, China.
2
Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Prevention and Cure Center of Breast Disease, Third Hospital of Nanchang, Nanchang 33009, China.
3
Prevention and Cure Center of Breast Disease, Third Hospital of Nanchang, Nanchang 33009, China.
4
Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
5
Prevention and Cure Center of Breast Disease, Third Hospital of Nanchang, Nanchang 33009, China. Electronic address: yalicao_nc@sina.com.
6
Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou 215021, China. Electronic address: fczhang2005@163.com.

Abstract

Recently, studies have been suggested that H3K27me3 is implicated with maintenance of cancer stem cells (CSCs), however, the roles of H3K27me3 in Breast cancer stem cells (BCSCs) remain poorly investigated. Here we explore the functionallities of H3K27me3 on BCSCs, we identify H3K27me3 as a negative modulator of BCSCs and suggest GSKJ4 is a promising drug targeting BCSCs. We show that the H3K27me3 level is decreased in mammosphere-derived BCSCs. In breast cancer cells, we demonstrate that GSKJ4 could markedly inhibit the proliferation. Strikingly, we show that GSKJ4 could effectively suppress BCSCs including expansion, self-renewal capacity, and the expression of stemness-related markers. Additionally, our xenograft model confirms that GSKJ4 is able to effectively inhibit the tumorigenicity of MDA-MB-231. Mechanistically, the inhibition effects of GSKJ4 on BCSCs are via inhibiting demethylases JMJD3 and UTX with methyltransferase EZH2 unchanged, which enhances H3K27me3 level. H3K27me3 activating leads to reduction of BCSCs expansion, self-renewal and global level of stemness factors. Collectively, our results provide strong supports that H3K27me3 exerts a suppressive influence on BCSCs and reveal that GSKJ4 is capable to be a prospective agent targeting BCSCs.

KEYWORDS:

Breast cancer stem cells; Epigenetic modification; GSKJ4; H3K27me3

PMID:
28823831
DOI:
10.1016/j.yexcr.2017.08.024
[Indexed for MEDLINE]

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