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

// Hui Ma 1, * , Li Li 1, * , Guojun Dou 1 , Chengqiang Wang 1 , Juan Li 1 , Hui He 1 , Mingxia Wu 1 and Hongyi Qi 1 1 College 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.