MZF-1/Elk-1 interaction domain as therapeutic target for protein kinase Cα-based triple-negative breast cancer cells

Chia Jen Lee, Li Sung Hsu, Chia Herng Yue, Ho Lin, Yung Wei Chiu, Yu Yu Lin, Chih Yang Huang, Mien Chie Hung, Jer Yuh Liu

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Recent reports demonstrate that the expression of protein kinase C alpha (PKCα) in triple-negative breast cancer (TNBC) correlates with decreased survival outcomes. However, off-target effects of targeting PKCα and limited understanding of the signaling mechanisms upstream of PKCα have hampered previous efforts to manipulate this ubiquitous gene. This study shows that the expression of both myeloid zinc finger 1 (MZF-1) and Ets-like protein-1 (Elk-1) correlates with PKCα expression in TNBC. We found that the acidic domain of MZF-1 and the heparinbinding domain of Elk-1 facilitate the heterodimeric interaction between the two genes before the complex formation binds to the PKCα promoter. Blocking the formation of the heterodimer by transfection of MZF-160-72 or Elk-1145-157 peptide fragments at the MZF-1 / Elk-1 interface decreases DNA-binding activity of the MZF-1 / Elk-1 complex at the PKCα promoter. Subsequently, PKCα expression, migration, tumorigenicity, and the epithelial-mesenchymal transition potential of TNBC cells decrease. These subsequent effects are reversed by transfection with full-length PKCα, confirming that the MZF-1/Elk-1 heterodimer is a mediator of PKCα in TNBC cells. These data suggest that the next therapeutic strategy in treating PKCα-related cancer will be developed from blocking MZF-1/Elk-1 interaction through their binding domain.

Original languageEnglish (US)
Pages (from-to)59845-59859
Number of pages15
JournalOncotarget
Volume7
Issue number37
DOIs
StatePublished - Jan 1 2016

Keywords

  • Elk-1
  • MZF-1
  • PKCα
  • Triple-negative breast cancer cells

ASJC Scopus subject areas

  • Oncology

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    Lee, C. J., Hsu, L. S., Yue, C. H., Lin, H., Chiu, Y. W., Lin, Y. Y., Huang, C. Y., Hung, M. C., & Liu, J. Y. (2016). MZF-1/Elk-1 interaction domain as therapeutic target for protein kinase Cα-based triple-negative breast cancer cells. Oncotarget, 7(37), 59845-59859. https://doi.org/10.18632/oncotarget.11337