Loss of epigenetic Kruppel-like factor 4 histone deacetylase (KLF-4-HDAC)-mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor (VEGF) expression in breast cancer.

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  • Author(s): Ray A;Ray A; Alalem M; Alalem M; Ray BK; Ray BK
  • Source:
    The Journal of biological chemistry [J Biol Chem] 2013 Sep 20; Vol. 288 (38), pp. 27232-27242. Date of Electronic Publication: 2013 Aug 06.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Epigenesis, Genetic* ; Gene Expression Regulation, Neoplastic* ; Promoter Regions, Genetic* ; Transcription, Genetic*; Breast Neoplasms/*metabolism ; Histone Deacetylase 2/*biosynthesis ; Histone Deacetylases/*biosynthesis ; Kruppel-Like Transcription Factors/*biosynthesis ; Neoplasm Proteins/*metabolism ; Repressor Proteins/*biosynthesis ; Vascular Endothelial Growth Factor A/*biosynthesis; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Line, Tumor ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Female ; Histone Deacetylase 2/genetics ; Histone Deacetylases/genetics ; Human Umbilical Vein Endothelial Cells ; Humans ; Kruppel-Like Factor 4 ; Kruppel-Like Transcription Factors/genetics ; Neoplasm Proteins/genetics ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Repressor Proteins/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Vascular Endothelial Growth Factor A/genetics
    • Abstract:
      Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation.
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    • Contributed Indexing:
      Keywords: Angiogenesis; Breast Cancer; DNA-Protein Interaction; Gene Regulation; Transcription Factors
    • Accession Number:
      0 (DNA-Binding Proteins)
      0 (KLF4 protein, human)
      0 (Kruppel-Like Factor 4)
      0 (Kruppel-Like Transcription Factors)
      0 (Neoplasm Proteins)
      0 (Repressor Proteins)
      0 (Transcription Factors)
      0 (VEGFA protein, human)
      0 (Vascular Endothelial Growth Factor A)
      0 (c-MYC-associated zinc finger protein)
      EC 3.5.1.98 (HDAC2 protein, human)
      EC 3.5.1.98 (Histone Deacetylase 2)
      EC 3.5.1.98 (Histone Deacetylases)
      EC 3.5.1.98 (histone deacetylase 3)
    • Publication Date:
      Date Created: 20130809 Date Completed: 20131126 Latest Revision: 20211203
    • Publication Date:
      20240829
    • Accession Number:
      PMC3779720
    • Accession Number:
      10.1074/jbc.M113.481184
    • Accession Number:
      23926105