LSD1 engages a corepressor complex for the activation of the estrogen receptor α by estrogen and cAMP

Nucleic Acids Res. 2016 Oct 14;44(18):8655-8670. doi: 10.1093/nar/gkw522. Epub 2016 Jun 20.

Abstract

The estrogen receptor α (ERα) is a transcription factor that can be directly activated by estrogen or indirectly by other signaling pathways. We previously reported that activation of the unliganded ERα by cAMP is mediated by phosphorylation of the transcriptional coactivator CARM1 by protein kinase A (PKA), allowing CARM1 to bind ERα directly. This being insufficient by itself to activate ERα, we looked for additional factors and identified the histone H3 demethylase LSD1 as a substrate of PKA and an important mediator of this signaling crosstalk as well as of the response to estrogen. Surprisingly, ERα engages not only LSD1, but its partners of the CoREST corepressor complex and the molecular chaperone Hsp90. The recruitment of Hsp90 to promote ERα transcriptional activity runs against the steroid receptor paradigm and suggests that it might be involved as an assembly factor or scaffold. In a breast cancer cell line, which is resistant to the anti-estrogen tamoxifen because of constitutively activated PKA, some interactions are constitutive and drug combinations partially rescue tamoxifen sensitivity. In ERα-positive breast cancer patients, high expression of the genes encoding some of these factors correlates with poor prognosis. Thus, these mechanisms might contribute to ERα-driven breast cancer.

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Co-Repressor Proteins / metabolism*
  • Cyclic AMP / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • HSP90 Heat-Shock Proteins / metabolism
  • Histone Deacetylases / metabolism
  • Histone Demethylases / metabolism*
  • Humans
  • Ligands
  • Models, Biological
  • Nerve Tissue Proteins / metabolism*
  • Phosphorylation / drug effects
  • Prognosis
  • Protein-Arginine N-Methyltransferases / metabolism
  • Substrate Specificity / drug effects
  • Transcription, Genetic / drug effects
  • Treatment Outcome

Substances

  • Co-Repressor Proteins
  • Estrogen Receptor alpha
  • Estrogens
  • HSP90 Heat-Shock Proteins
  • Ligands
  • Nerve Tissue Proteins
  • RCOR1 protein, human
  • estrogen receptor alpha, human
  • Cyclic AMP
  • Histone Demethylases
  • KDM1A protein, human
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1
  • Cyclic AMP-Dependent Protein Kinases
  • Histone Deacetylases