Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter.
Che-1 is a recently identified human RNA polymerase II binding protein involved in the regulation of gene transcription and cell proliferation. We previously demonstrated that Che-1 inhibits the Rb growth-suppressing function by interfering with Rb-mediated HDAC1 recruitment on E2F target gene promoters. By hybridization of cancer profile arrays, we found ... that Che-1 expression is strongly down-regulated in several tumors, including colon and kidney carcinomas, compared with the relative normal tissues. Consistent with these data, Che-1 overexpression inhibits proliferation of HCT116 and LoVo human colon carcinoma cell lines by activation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 in a p53-independent manner and by promoting growth arrest at the G1 phase of the cell cycle. Che-1 activates p21WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21WAF1/Cip1 gene promoter and accumulating acetylated histone H3 on these sites. Accordingly, Che-1-specific RNA interference negatively affects p21WAF1/Cip1 transactivation and increases cell proliferation in HCT116 cells. Taken together, our results indicate that Che-1 can be considered a general HDAC1 competitor and its down-regulation is involved in colon carcinoma cell proliferation.
Mesh Terms:
Base Sequence, Binding, Competitive, Blotting, Western, Cell Division, Cell Line, Tumor, Chromatin, Colonic Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, Dose-Response Relationship, Drug, Down-Regulation, Glutathione Transferase, Histone Deacetylase 1, Histone Deacetylases, Histones, Humans, Microscopy, Fluorescence, Models, Genetic, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Sp1 Transcription Factor, Time Factors, Tissue Distribution, Transcriptional Activation, Transfection, Tumor Suppressor Protein p53
Base Sequence, Binding, Competitive, Blotting, Western, Cell Division, Cell Line, Tumor, Chromatin, Colonic Neoplasms, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, Dose-Response Relationship, Drug, Down-Regulation, Glutathione Transferase, Histone Deacetylase 1, Histone Deacetylases, Histones, Humans, Microscopy, Fluorescence, Models, Genetic, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Sp1 Transcription Factor, Time Factors, Tissue Distribution, Transcriptional Activation, Transfection, Tumor Suppressor Protein p53
J. Biol. Chem.
Date: Sep. 19, 2003
PubMed ID: 12847090
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