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J. Biol. Chem., Vol. 278, Issue 38, 36496-36504, September 19, 2003

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Che-1 Arrests Human Colon Carcinoma Cell Proliferation by Displacing HDAC1 from the p21^WAF1/CIP1 Promoter^*

Monica Di Padova  , Tiziana Bruno , Francesca De Nicola  ¶, Simona Iezzi , Carmen D'Angelo ||, Rita Gallo ¶, Daniela Nicosia ¶, Nicoletta Corbi  **, Annamaria Biroccio ||, Aristide Floridi  ¶, Claudio Passananti ** and Maurizio Fanciulli  

From the Laboratory B and the ^||Experimental Chemotherapy Laboratory, Experimental Research Center, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, the ^¶Department of Experimental Medicine, Via Vetoio, Coppito 2, University of L'Aquila, 67100 L'Aquila, and the ^**Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, Viale Marx 43, 00137 Rome, Italy

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^WAF1/Cip1 in a p53-independent manner and by promoting growth arrest at the G₁ phase of the cell cycle. Che-1 activates p21^WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21^WAF1/Cip1 gene promoter and accumulating acetylated histone H3 on these sites. Accordingly, Che-1-specific RNA interference negatively affects p21^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.

Received for publication, June 24, 2003 , and in revised form, July 2, 2003.

^* This work was supported by the Italian Association for Cancer Research (A.I.R.C.), Italian Ministry of Health (Ministero della Sanità), Telethon project A160, and Ministero Istruzione Università e Ricerca. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of an Italian Federation for Cancer Research fellowship.

To whom correspondence should be addressed. Tel.: 3906-52662566; Fax: 3906-52662566; E-mail: fanciulli{at}.ifo.it.

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