title: Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90.
abstract: OBJECTIVE
  The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-alpha in an active conformation, allowing it to bind 17beta-estradiol (E2) and transactivate genes, including progesterone receptor (PR)-beta 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 alpha-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 ERalpha, as well as on the survival of ERalpha-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells.
  
  
  METHODS
  Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERalpha, 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 ERalpha, and increased polyubiquitylation and depletion of ERalpha levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRbeta 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 ERalpha-positive breast cancer cells to tamoxifen.
  
  
  CONCLUSIONS
  These findings show that treatment with HA-HDI abrogates ERalpha levels and activity and could sensitize ERalpha-positive breast cancers to E2 depletion or ERalpha antagonists.
authors: Medical College of Georgia Cancer Center, Augusta, Georgia 30912, USA.
authors: Warren
authors: W
authors: Fiskus
authors: Yuan
authors: Y
authors: Ren
authors: Alex
authors: A
authors: Mohapatra
authors: Purva
authors: P
authors: Bali
authors: Aditya
authors: A
authors: Mandawat
authors: Rekha
authors: R
authors: Rao
authors: Bryan
authors: B
authors: Herger
authors: Yonghua
authors: Y
authors: Yang
authors: Peter
authors: P
authors: Atadja
authors: Jie
authors: J
authors: Wu
authors: Kapil
authors: K
authors: Bhalla
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000032:analysis* / Q000037:antagonists & inhibitors; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000032:analysis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013629:Tamoxifen; C016601:afimoxifene; D011065:Poly(ADP-ribose) Polymerases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases