Latent transforming growth factor β-binding protein 4 is downregulated in esophageal cancer via promoter methylation

PLoS One. 2013 May 31;8(5):e65614. doi: 10.1371/journal.pone.0065614. Print 2013.


Latent transforming growth factor β-binding protein 4 (LTBP4) is an extracellular matrix molecule that is a member of important connective tissue networks and is needed for the correct folding and the secretion of TGF-β1. LTBP4 is downregulated in carcinomas of various tissues. Here we show that LTBP4 is also downregulated in adenocarcinomas and squamous cell carcinomas of the esophagus in vitro and in vivo. Re-expression of LTBP4 in esophageal cancer cell lines reduced cell migration ability, whereas cell viability and cell proliferation remained unchanged. Hypermethylation of the promoter regions of the two main human LTBP4 transcriptional forms, LTBP4L and LTBP4S, was found to be involved in LTBP4 silencing. Detailed investigations of the methylation patterns of the promoter regions of LTBP4L and LTBP4S identified GATA1, SP1, E2F4 and SMAD3 as potential transcription factors involved in LTBP4 expression. In in vitro transcription factor activity studies we discovered E2F4 as novel powerful regulator for LTBP4S expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Base Sequence
  • Binding Sites
  • Carcinoma / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • DNA Methylation*
  • Decitabine
  • Disease Progression
  • Down-Regulation
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Gene Order
  • Humans
  • Latent TGF-beta Binding Proteins / genetics*
  • Neoplasm Staging
  • Promoter Regions, Genetic*
  • Protein Binding
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta1 / genetics


  • LTBP4 protein, human
  • Latent TGF-beta Binding Proteins
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Decitabine
  • Azacitidine

Grant support

This work was supported by the Maria Pesch-Foundation (National Science Funding Organisation). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.