Histone deacetylase inhibitors upregulate MMP11 gene expression through Sp1/Smad complexes in human colon adenocarcinoma cells

Juan I Barrasa, Nieves Olmo, Angélica Santiago-Gómez, Emilio Lecona, Patrick Anglard, Javier Turnay, M Antonia Lizarbe

Research output: Contribution to journalArticlepeer-review

Abstract

MMP-11 (stromelysin-3) is a matrix metalloproteinase associated with tumor progression and poor prognosis. Its expression was initially described exclusively in stromal cells surrounding tumors, but more recently it has also been detected in macrophages and hepatocarcinoma cells. Here we show MMP-11 expression in human epithelial colon adenocarcinoma cell lines (Caco-2, HT-29 and BCS-TC2). Treatment of BCS-TC2 cells with butyrate and trichostatin A (TSA) (histone deacetylase inhibitors) increases MMP11 promoter activity and protein expression. Using electrophoretic mobility shift assay (EMSA) and supershift assays, we demonstrate for the first time that Sp1 is able to bind to the GC-boxes within the MMP11 proximal promoter region; this binding has been confirmed by chromatin immunoprecipitation. Sp1 is involved in MMP11 basal expression and it is essential for the upregulation of transcription by histone deacetylase inhibitors as deduced from mutant constructs lacking the Sp1 sites and by inhibition of its binding to the promoter with mithramycin. This regulation requires the formation of Sp1/Smad2 heterocomplexes, which is stimulated by an increase in the acetylation status of Smad after butyrate or TSA treatments. We have also found that ERK1/2-mitogen-activated protein kinase (MAPK), but not p38-MAPK or JNK, is involved in the upregulation of MMP11 by HDAC inhibitors.

Original languageEnglish
Pages (from-to)570-81
Number of pages12
JournalBiochimica et biophysica acta
Volume1823
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Adenocarcinoma
  • Butyrates
  • Cell Line, Tumor
  • Colonic Neoplasms
  • Gene Expression
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids
  • Matrix Metalloproteinase 11
  • Mitogen-Activated Protein Kinases
  • Promoter Regions, Genetic
  • Smad Proteins
  • Sp1 Transcription Factor
  • Journal Article
  • Research Support, Non-U.S. Gov't

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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