Timosaponin A-III inhibits oncogenic phenotype via regulation of PcG protein BMI1 in breast cancer cells

Mol Carcinog. 2018 Jul;57(7):831-841. doi: 10.1002/mc.22804. Epub 2018 Mar 25.

Abstract

Polycomb group (PcG) protein BMI1 is an important regulator of oncogenic phenotype and is often overexpressed in several human malignancies including breast cancer. Aberrant expression of BMI1 is associated with metastasis and poor prognosis in cancer patients. At present, therapy reagents that can efficiently inhibit the expression of BMI1 are not very well known. Here, we report that Timosaponin A-III (TA-III), a steroidal saponin obtained from the rhizomes of an herb, Anemarrhena asphodeloides, strongly inhibits expression of BMI1 in breast cancer cells. Treatment of breast cancer cells with TA-III resulted in inhibition of oncogenic phenotypes such as proliferation, migration and invasion, and induction of cellular senescence. Inhibition of these oncogenic phenotypes was accompanied by downregulation of BMI1 expression and histone posttranslational modification activity of PRC1. The mechanistic analysis of TA-III-induced inhibition of oncogenic activity and BMI1 expression suggests that downregulation of c-Myc mediates TA-III effect on BMI1. We further show that exogenous BMI1 overexpression can overcome TA-III-induced inhibition of oncogenic phenotypes. We also show that TA-III induces expression of tumor suppressive miR-200c and miR-141, which are negatively regulated by BMI1. In summary, our data suggest that TA-III is a potent inhibitor of BMI1 and that it can be successfully used to inhibit the growth of tumors where PcG protein BMI1 and PcG activities are upregulated.

Keywords: BMI1; Timosaponin A-III; breast cancer; cellular senescence; miR-141; miR-200c; polycomb group proteins; tumor suppressors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Carcinogenesis / drug effects*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MCF-7 Cells
  • MicroRNAs / genetics
  • Oncogenes / genetics
  • Phenotype
  • Polycomb Repressive Complex 1 / genetics*
  • Polycomb-Group Proteins / genetics*
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / genetics
  • Saponins / pharmacology*
  • Steroids / pharmacology*

Substances

  • BMI1 protein, human
  • MicroRNAs
  • Polycomb-Group Proteins
  • Saponins
  • Steroids
  • timosaponin AIII
  • Polycomb Repressive Complex 1