Oncotarget

Research Papers:

Z-ligustilide restores tamoxifen sensitivity of ERα negative breast cancer cells by reversing MTA1/IFI16/HDACs complex mediated epigenetic repression of ERα

Hui Ma, Li Li, Guojun Dou, Chengqiang Wang, Juan Li, Hui He, Mingxia Wu and Hongyi Qi _

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Oncotarget. 2017; 8:29328-29345. https://doi.org/10.18632/oncotarget.16440

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Abstract

Hui Ma1,*, Li Li1,*, Guojun Dou1, Chengqiang Wang1, Juan Li1, Hui He1, Mingxia Wu1 and Hongyi Qi1

1College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China

*These authors have contributed equally to this work

Correspondence to:

Hongyi Qi, email: hongyiqi@swu.edu.cn

Keywords: Z-ligustilide, tamoxifen, ERα negative breast cancer, MTA1, histone modification

Received: January 13, 2017     Accepted: March 02, 2017     Published: March 22, 2017

ABSTRACT

Emerging evidence indicates epigenetic modification represses estrogen receptor α (ERα) and contributes to the resistance to tamoxifen in aggressive ERα-negative (ERα-) breast cancer. Z-ligustilide is a major compound in Radix Angelica sinensis, an herb from traditional Chinese medicine (TCM) most frequently prescribed for breast cancer. However, the role of Z-ligustilide in ERα- breast cancer and epigenetic modification remains largely unknown. Herein we showed, for the first time, that Z-ligustilide restored the growth inhibition of tamoxifen on ERα- breast cancer cells. Apoptosis and S and G2/M phases cell cycle arrest were induced by combinatorial Z-ligustilide and tamoxifen. Importantly, Z-ligustilide reactivated the ERα expression and transcriptional activity, which is proved to be indispensable for restoring the sensitivity to tamoxifen. Interestingly, Z-ligustilide increased Ace-H3 (lys9/14) enrichment in the ERα promoter. Moreover, Z-ligustilide dramatically reduced the enrichment of metastasis-associated protein 1 (MTA1) as well as IFN-γ-inducible protein 16 (IFI16) and histone deacetylases (HDACs) onto the ERα promoter. Meanwhile, Z-ligustilide downregulated MTA1, IFI16 and HDACs, which caused destabilization of the corepressor complex. Collectively, our study not only highlights Z-ligustilide as a novel epigenetic modulator, but also opens new possibilities from TCM for treating aggressive tamoxifen-resistant breast cancer.


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