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

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.

Transcription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A

“…embryogenesis (21,22,26). Because initial studies of the role of MZF1 in myeloid differentiation and leukemia (18,23), it has been demonstrated that the MZF1-dependent transcriptional changes occur in malignant cellular processes (24,27,28,30,(36)(37)(38)(39)(40)(41)(42)(43), and aberrant expression of MZF1 correlates with poor prognosis of several types of cancers (29,32,34,44,45). However, the contribution of MZF1 to tumorigenesis has not been fully elucidated (20).…”

Zinc Finger Transcription Factor MZF1—A Specific Regulator of Cancer Invasion

“…This domain is involved in transcriptional activation and contains regulatory SUMO and phospho-sites [22]. It can also mediate interactions between MZF1 and other transcription factors [22][23][24]. Downstream of the acidic domain is the SCAN domain of 84 amino acids, a leucine-rich region known to mediate protein-protein interactions [16,17,25,26].…”

“…Recent work has indicated that the acidic domain of MZF1 is an additional protein-protein interaction domain. The acidic domain of MZF1 is involved in its association with Elk1 in triple negative breast cancer [12,23,24]. Association of MZF1 and Elk1 via the acidic domain of MZF1 and the heparin-binding domain of Elk1 increases invasion, migration and mesenchymal phenotype of breast cancer cells.…”

GT198 (PSMC3IP) germline variants in early-onset breast cancer patients from hereditary breast and ovarian cancer families

“…ELK1 overexpression is frequently observed in many carcinomas, including breast cancer [36]. Recently, the MZF1/Elk-1 complex has been identified as mediator of protein kinase C alpha (PKCα) expression in triple-negative breast cancer, which induces cell migration and invasion of triple negative breast cancer cells and poor outcome [37]. However, the pathogenic effect of altered GT198 expression in general and the influence of c.-115G>A on GT198 expression in breast or ovary in vivo is still unknown and requires further elucidation.…”