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

ABSTRACT: Recent reports demonstrate that the expression of protein kinase C alpha (PKC?) in triple-negative breast cancer (TNBC) correlates with decreased survival outcomes. However, off-target effects of targeting PKC? and limited understanding of the signaling mechanisms upstream of PKC? 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 PKC? expression in TNBC. We found that the acidic domain of MZF-1 and the heparin-binding domain of Elk-1 facilitate the heterodimeric interaction between the two genes before the complex formation binds to the PKC? 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 PKC? promoter. Subsequently, PKC? expression, migration, tumorigenicity, and the epithelial-mesenchymal transition potential of TNBC cells decrease. These subsequent effects are reversed by transfection with full-length PKC?, confirming that the MZF-1/Elk-1 heterodimer is a mediator of PKC? in TNBC cells. These data suggest that the next therapeutic strategy in treating PKC?-related cancer will be developed from blocking MZF-1/Elk-1 interaction through their binding domain.

SUBMITTER: Lee CJ 

PROVIDER: S-EPMC5312353 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature