Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-α levels and transcriptional activity: A result of hyperacetylation and inhibition of chaperone function of heat shock protein 90

Warren Fiskus, Yuan Ren, Alex Mohapatra, Purva Bali, Aditya Mandawat, Rekha Rao, Bryan Herger, Yonghua Yang, Peter Atadja, Jie Wu, Kapil Bhalla

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

Purpose: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-α in an active conformation, allowing it to bind 17β-estradiol (E2) and transactivate genes, including progesterone receptor (PR)-β and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates α-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ERα, as well as on the survival of ERα-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells. Experimental Design: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERα, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells. Results: Treatment with HA-HDI induced hsp90 hyperacetylation, decreased its binding to ERα, and increased polyubiquitylation and depletion of ERα levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRβ and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal-regulated kinase-1/2 levels, inhibited growth, and sensitized ERα-positive breast cancer cells to tamoxifen. Conclusions: These findings show that treatment with HA-HDI abrogates ERα levels and activity and could sensitize ERα-positive breast cancers to E2 depletion or ERα antagonists.

Original languageEnglish (US)
Pages (from-to)4882-4890
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number16
DOIs
StatePublished - Aug 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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