Hsp90 inhibition suppresses NF-ĸB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells

Gagan S. Thangjam, Charalampos Birmpas, Nektarios Barabutis, Betsy W. Gregory, Mary Ann Clemens, Joseph R. Newton, David Fulton, John D. Catravas

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-ĸB-mediated transcription is the major basis for their anti-inflammatory properties. While the molecular mechanisms underlying this effect are not clear, they appear to be distinct in human endothelial cells. We now show for the first time that type 2 sirtuin (Sirt-2) histone deacetylase binds human NF-ĸB target gene promoter and prevents the recruitment of NF-ĸB proteins and subsequent assembly of RNA polymerase II complex in human lung microvascular endothelial cells. Hsp90 inhibitors stabilize the Sirt-2/promoter interaction and impose a “transcriptional block,” which is reversed by either inhibition or downregulation of Sirt-2 protein expression. Furthermore, this process is independent of NF-ĸB (p65) Lysine 310 deacetylation, suggesting that it is distinct from known Sirt-2-dependent mechanisms. We demonstrate that Sirt-2 is recruited to NF-ĸB target gene promoter via interaction with core histones. Upon inflammatory challenge, chromatin remodeling and core histone H3 displacement from the promoter region removes Sirt-2 and allows NF-ĸB/coactivator recruitment essential for RNA Pol II-dependent mRNA induction. This novel mechanism may have important implications in pulmonary inflammation.

Original languageEnglish (US)
Pages (from-to)L964-L974
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume310
Issue number10
DOIs
StatePublished - May 15 2016

Keywords

  • Histone h3
  • Hsp90
  • Human lung endothelial cells
  • NF-ĸB
  • Sirt-2

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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