Che-1 Arrests Human Colon Carcinoma Cell Proliferation by Displacing HDAC1 from the p21WAF1/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,Maurizio Fanciulli

doi:10.1074/jbc.m306694200

Abstract

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.

Highlights

Che-1 is a recently identified human RNA polymerase II binding protein involved in the regulation of gene transcription and cell proliferation
Our results indicate that Che-1 can be considered a general HDAC1 competitor and its down-regulation is involved in colon carcinoma cell proliferation
The data presented here show a specific involvement of Che-1 expression in the growth arrest of human colon carcinoma cell lines, exerted by p21 induction

Summary

Introduction

Che-1 is a recently identified human RNA polymerase II binding protein involved in the regulation of gene transcription and cell proliferation. 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/Cip in a p53-independent manner and by promoting growth arrest at the G1 phase of the cell cycle. Histone acetyl transferases and histone deacetylases (HDACs) affect gene expression by regulating the acetylation of histone and non-histone proteins [1,2,3], and HDAC inhibitors, such as sodium butyrate, trichostatin A, or suberoylanilide hydroxamic acid, inhibit proliferation of several tumor cell lines and tumor growth in vivo (4 –10). As the E2F pathway is activated in highly proliferative cancer cells, we might expect Che-1 levels to be altered

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