Abstract
In this study, the molecular mechanism of protein kinase C alpha (PKCα) gene regulation in hepatocellular carcinoma (HCC) involving Ets-like protein-1 (Elk-1) and myeloid zinc finger-1 (MZF-1) was investigated. The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity, and the transcriptional activity decreased when the transfection included a DNA-binding-deficient (∆DBD) gene vector of either MZF-1 or Elk-1 DNA-binding deficiency (MZF-1∆DBD or Elk-1∆DBD), thereby indicating that the enhanced expression of PKCα was caused by the binding of MZF-1 and/or Elk-1 with the PKCα promoter. We investigated MZF-1 and Elk-1 to determine whether they bind to each other. The results of immunoprecipitation (IP), Co-IP, chromatin IP (ChIP), and Re-ChIP analyses indicated that Elk-1 can directly bind to the N-terminal region of MZF-1 and MZF-1 can directly bind to the C-terminal region of Elk-1 to form a complex before attaching to the PKCα promoter. Furthermore, when MZF-1∆DBD or Elk-1∆DBD was added to the cells, PKCα expression decreased, and cell proliferation, migration, invasion, and tumorigenicity also decreased. These findings suggest that PKCα expression in HCC could be stimulated by the formation of MZF-1/Elk-1 complex, which directly binds to the PKCα promoter.
Highlights
Protein kinase C alpha (PKCα), one of the proteins in the kinase C family, is generally known to serve an important function in tumorigenesis, invasion, and metastasis [1,2,3]
This study uses the human hepatocellular carcinoma (HCC) model to demonstrate that myeloid zinc finger-1 (MZF-1) and Ets-like protein-1 (Elk-1) directly bind to the PKCα promoter and modulate PKCα performance through the interactive cooperation between the two transcription factors
To check if the enhanced level of both Elk-1 and MZF-1 were synergistically responsible for the increase in transcriptional activity of PKCα promoter, a luciferase assay was performed in the same cell-lines
Summary
Protein kinase C alpha (PKCα), one of the proteins in the kinase C family, is generally known to serve an important function in tumorigenesis, invasion, and metastasis [1,2,3]. Our recent studies found that two transcription genes, namely, Ets-like protein-1 (Elk-1) and myeloid zinc finger-1 (MZF-1), can regulate PKCα expression [5,6,7]. These genes are viable targets for new PKCα inhibition strategies. MZF-1 is preferentially expressed in myeloid progenitor cells [12] and is involved in the growth, differentiation, and apoptosis of myeloid progenitors [13,14,15] Both MZF-1 and Elk-1 gene expressions have been found to be associated with PKCα in liver cancer cells [5,6,7], thereby suggesting that these transcription factors in PKCα cooperate in influencing carcinogenesis. This study aims to delineate in greater detail the molecular mechanism underlying PKCα gene regulation by Elk-1 and MZF-1
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