Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors

Cancer Cell. 2009 Apr 7;15(4):283-93. doi: 10.1016/j.ccr.2009.02.015.

Abstract

NF-kappaB (RelA) is constitutively active in many cancers, where it upregulates antiapoptotic and other oncogenic genes. While proinflammatory stimulus-induced NF-kappaB activation involves IKK-dependent nuclear translocation, mechanisms for maintaining constitutive NF-kappaB activity in tumors have not been elucidated. We show here that maintenance of NF-kappaB activity in tumors requires Stat3, which is also frequently constitutively activated in cancer. Stat3 prolongs NF-kappaB nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-kappaB nuclear export. Stat3-mediated maintenance of NF-kappaB activity occurs in both cancer cells and tumor-associated hematopoietic cells. Both murine and human cancers display highly acetylated RelA, which is associated with Stat3 activity. This Stat3/NF-kappaB interaction is thus central to both the transformed and nontransformed elements in tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Active Transport, Cell Nucleus
  • Animals
  • Electrophoretic Mobility Shift Assay
  • Fluorescent Antibody Technique
  • Hematopoietic System / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Integrases / metabolism
  • Male
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • STAT3 Transcription Factor / physiology*
  • Signal Transduction
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*

Substances

  • NF-kappa B
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Cre recombinase
  • Integrases
  • Histone Deacetylases