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Poster display session

2053 - GSKJ4, an H3K27me3 demethylase inhibitor, effectively suppresses the breast cancer stem cells

Date

11 Sep 2017

Session

Poster display session

Topics

Cancer Biology;  Breast Cancer

Presenters

Ning Yan

Citation

Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361

Authors

N. Yan1, Y. Cao2, L. Xu1, F.C. Zhang1

Author affiliations

  • 1 Oncology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, College of Medicine, 200025 - Shanghai/CN
  • 2 Prevention And Cure Center Of Breast Disease, Third Hospital of Nanchang, 33009 - Nanchang/CN
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Resources

Abstract 2053

Background

Breast cancer stem cells (BCSCs) are responsible for breast cancer metastasis and treatment failure. Hence, eliminating BCSCs poses possibility to eradicate breast cancer. Recently, studies have been suggested that H3K27me3 is implicated in maintenance of cancer stem cells (CSCs), however, the roles of H3K27me3 in BCSCs remain poorly investigated. Hence, we aimed to explore the functionality of H3K27me3 in BCSCs.

Methods

Here, we firstly determined the global level of H3K27me3 in mammosphere-derived cells. Then, we detected the effect of GSKJ4 in cell viability through CCK8 assay. Next, we tested the impact of GSKJ4 on BCSCs expansions with CD44+CD24- phenotype and ALDH1-positive via flowcytometry. In addition, the impact on self-renewal capacity of BCSCs were also asked using mammosphere formation assay and colony formation assay. Further, western blot and Q-PCR were conducted to explore the effect of GSKJ4 in the expression level of stemness-related markers. Finally, we determined the influence of GSKJ4 on tumorigenicity using a xenograft model and investigated the underlying mechanisms.

Results

We identify H3K27me3 as a negative modulator of stemness 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 its 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 effect of GSKJ4 in BCSCs is via inhibiting JMJD3 and UTX thus causing increment of H3K27me3 level, which results in suppressing stemness factors including NANOG, SOX2 and OCT4.

Conclusions

Our results provide strong supports that epigenetic modification is associated with maintenance of properties of BCSCs and reveal that GSKJ4 is capable to be a prospective agent targeting BCSCs.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

None

Disclosure

All authors have declared no conflicts of interest.

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