Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity

• LSD1 is broadly associated with AR-regulated enhancers, and a subset is H3T6ph marked
• LSD1 is associated with CoREST at these sites and interacts with FOXA1
• Despite coactivator function at these sites, LSD1 mediates their H3K4 demethylation
• LSD1 coactivation is through demethylation of novel histone or nonhistone substrates

SummaryLysine-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.

Graphical AbstractFigure optionsDownload as PowerPoint slide