Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter

J Biol Chem. 2003 Sep 19;278(38):36496-504. doi: 10.1074/jbc.M306694200. Epub 2003 Jul 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding, Competitive
  • Blotting, Western
  • Cell Division
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Colonic Neoplasms / pathology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Glutathione Transferase / metabolism
  • Histone Deacetylase 1
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • 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 / metabolism
  • Time Factors
  • Tissue Distribution
  • Transcriptional Activation
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • CDKN1A protein, human
  • Chromatin
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Histones
  • Sp1 Transcription Factor
  • Tumor Suppressor Protein p53
  • Glutathione Transferase
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases