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Hif2 alpha-sp1 interaction mediates a deacetylation-dependent fvii-gene activation under hypoxic conditions in ovarian cancer cells

Academic Article
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Overview

authors

  • Koizume, S.
  • Ito, S.
  • Miyagi, E.
  • Hirahara, F.
  • Nakamura, Y.
  • Sakuma, Y.
  • Osaka, H.
  • Takano, Y.
  • Ruf, Wolfram
  • Miyagi, Y.

publication date

  • July 2012

journal

  • Nucleic Acids Research  Journal

abstract

  • Hypoxia-inducible factors (HIF)-1α and HIF2α are major transcription factors required for adaptive responses to hypoxia. HIFs form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) to bind to the regulatory regions of target genes. The acetylation of histones by histone acetyltransferases (HATs) is one of the epigenetic marks associated with active chromatin. Indeed, HIFs recruit p300 HAT to hypoxia response elements (HREs) within gene regulatory regions. Here, we report an unusual HIF-mediated transcriptional activation in ovarian clear cell carcinoma (CCC). While characterizing coagulation factor VII (FVII) gene induction during hypoxic conditions, we observed that the interaction of HIF2α with Sp1, but not with ARNT, could induce transcription of FVII in a HRE-independent manner. Unexpectedly, this gene activation is associated with histone deacetylation. We found that a class II HDAC, HDAC4, is recruited with HIF2α to the FVII promoter as a co-activator, while p300 HAT negatively regulated this process. Furthermore, this mechanism can be synergistically enhanced via a deacetylation-dependent pathway when cells are simultaneously exposed to hypoxic and serum-free conditions. These results suggest the presence of a stress-responsive transcription mediated by the HIF2α/Sp1/HDAC4 network and explain how CCC shed their procoagulant activity under hypoxia.

subject areas

  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Basic Helix-Loop-Helix Transcription Factors
  • Binding Sites
  • Cell Hypoxia
  • Cell Line, Tumor
  • Culture Media, Serum-Free
  • Factor VII
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glucose
  • Histone Deacetylases
  • Humans
  • Ovarian Neoplasms
  • Repressor Proteins
  • Sp1 Transcription Factor
  • Transcriptional Activation
  • Unfolded Protein Response
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Identity

PubMed Central ID

  • PMC3384323

International Standard Serial Number (ISSN)

  • 0305-1048

Digital Object Identifier (DOI)

  • 10.1093/nar/gks201

PubMed ID

  • 22402494
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Additional Document Info

start page

  • 5389

end page

  • 5401

volume

  • 40

issue

  • 12

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