Oncotarget

Research Papers:

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 and Jer-Yuh Liu _

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Oncotarget. 2016; 7:59845-59859. https://doi.org/10.18632/oncotarget.11337

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Abstract

Chia-Jen Lee1, Li-Sung Hsu2,3, Chia-Herng Yue4,5, Ho Lin5, Yung-Wei Chiu6, Yu-Yu Lin7, Chih-Yang Huang8,9,10, Mien-Chie Hung1,7,11, Jer-Yuh Liu1,7

1Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan

2Institute of Biochemistry, Microbiology and Immunology, Medical College, Chung-Shan Medical University, Taichung 40201, Taiwan

3Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

4Department of Surgery, Tungs’ Taichung Metro Harbor Hospital, Taichung 435, Taiwan

5Department of Life Science, National Chung Hsing University, Taichung 402, Taiwan

6Emergency Department and Center of Hyperbaric Oxygen Therapy, Tungs’ Taichung Metro Harbor Hospital, Taichung 435, Taiwan

7Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan

8Graduate Institute of Chinese Medical Science, School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

9Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan

10Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan

11Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

Correspondence to:

Jer-Yuh Liu, email: jyl@mail.cmu.edu.tw

Mien-Chie Hung, email: mhung@mdanderson.org

Chih-Yang Huang, email: cyhuang@mail.cmu.edu.tw

Keywords: MZF-1, Elk-1, PKCα, triple-negative breast cancer cells

Received: December 09, 2015     Accepted: July 06, 2016     Published: August 17, 2016

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 heparin-binding 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.


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