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.
Di Padova
Monica
M
Laboratory B.
Bruno
Tiziana
T
De Nicola
Francesca
F
Iezzi
Simona
S
D'Angelo
Carmen
C
Gallo
Rita
R
Nicosia
Daniela
D
Corbi
Nicoletta
N
Biroccio
Annamaria
A
Floridi
Aristide
A
Passananti
Claudio
C
Fanciulli
Maurizio
M
D001483:Base Sequence; D001667:Binding, Competitive; D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006657:Histones; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D005982:Glutathione Transferase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases