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

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.

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

“…Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from mono and dimethyl Lysine 4 of histone H3 (H3K4me1/2) and can contribute to gene silencing (38)(39)(40)(41). Since its discovery, LSD1 histone demethylase activity has been investigated as a pharmacologic target for cancer and other diseases.…”

Advances Toward Lsd1 Inhibitors for Cancer Therapy

“…[5,6,7]. Mounting evidences have shown that LSD1 mediates many cellular signaling pathways [8,9,10] and plays critical roles in regulating fundamental cellular processes (for part of LSD1-mediated biological processes, see Figure 1A) [11,12,13]. The diverse biological roles of LSD1 may explain why its dysfunction is associated with initiation and development of several diseases such as cancers, neurodegenerative diseases, cardiovascular diseases, inflammation, viral infections, etc.…”

Cellular analysis of the action of epigenetic drugs and probes

“…However, this challenge can be avoided when the function of a target enzyme as a mediator in a signal pathway is used for the regulation of the promoter of a reporter gene, e.g., reporter constructs of the TGFb signaling pathway for HDAC inhibitor screenings. 79 As LSD1 is involved in estrogen-and androgen-receptor regulation, ERa- 80 and androgen-receptor 81 -dependent luciferase assays have been developed. Once a reporter assay has been established, screening can be done easily and high-throughput assays are possible, which was implemented by Ashburner et al 82 with a NF-kB-dependent reporter gene.…”