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

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.

• Authors: Hui Ma, Li Li, Guojun Dou, Chengqiang Wang, Juan Li, Hui He, Mingxia Wu, Hongyi Qi
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 17 Pg. 29328-29345 (Apr 25 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28415616 (Publication Type: Journal Article)

Chemical References

• Tamoxifen
• ligustilide
• HDAC1 protein, human
• Histone Deacetylase 1
• 4-Butyrolactone

Topics

• 4-Butyrolactone (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Epigenesis, Genetic (drug effects)
• Epigenetic Repression (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase 1 (metabolism)
• Humans
• Tamoxifen (therapeutic use)