Che-1 Arrests Human Colon Carcinoma Cell Proliferation by Displacing HDAC1 from the p21 super(WAF1/CIP1) Promoter

• Published in: The Journal of biological chemistry 2003-09, Vol.278 (38), p.36496-36504
• Main Authors: Padova, MD, Bruno, T, De Nicola, F, Iezzi, S, D'Angelo, C, Gallo, R, Nicosia, D, Corbi, N, Biroccio, A, Floridi, A, Passananti, C, Fanciulli, M
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M306694200

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 p21 super(WAF1/Cip1) in a p53-independent manner and by promoting growth arrest at the G sub(1) phase of the cell cycle. Che-1 activates p21 super(WAF1/Cip1) by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21 super(WAF1/Cip1) gene promoter and accumulating acetylated histone H3 on these sites. Accordingly, Che-1-specific RNA interference negatively affects p21 super(WAF1/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.