Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity

Cell Rep. 2014 Dec 11;9(5):1618-1627. doi: 10.1016/j.celrep.2014.11.008. Epub 2014 Dec 4.


Lysine-Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4) but has a coactivator function on some genes through mechanisms that are unclear. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR-regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show that LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and that it has a distinct AR-linked coactivator function mediated by demethylation of other substrates.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Consensus Sequence
  • Enhancer Elements, Genetic
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Histone Demethylases / physiology*
  • Histones / metabolism
  • Humans
  • Methylation
  • Protein Processing, Post-Translational
  • Receptors, Androgen / physiology*
  • Transcription, Genetic
  • Transcriptional Activation


  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Histones
  • Receptors, Androgen
  • Histone Demethylases
  • KDM1A protein, human