Modulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells

• Published in: Molecular cancer research Vol. 6; no. 7; p. 1204
• Main Authors: Liu, Pei-Yao, Chan, James Yi-Hsin, Lin, Hsiu-Chen, Wang, Sung-Ling, Liu, Shu-Ting, Ho, Ching-Liang, Chang, Li-Chien, Huang, Shih-Ming
• Format: Journal Article
• Language: English
• Published: United States 01.07.2008
• Subjects: Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cercopithecus aethiops; COS Cells; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Down-Regulation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Genes, Reporter; HeLa Cells; Histone Deacetylase 1; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - pharmacology; Models, Biological; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - drug effects; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-08-0123

Zac1 is a novel seven-zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21(WAF1/Cip1) promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21(WAF1/Cip1) gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A-induced p21(WAF1/Cip1) protein expression might be mediated through a p53-independent and HDAC deacetylase-independent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21(WAF1/Cip1) gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.