GSE130067
Transcriptomic response of LSD1-UTX inhibitor on human breast cancer MCF7 cells
In many human cancers, including breast and prostate cancers, LSD1 and other lysine demethylases (KDMs), such as UTX, are co-expressed and co-localize with androgen receptors (AR) and estrogen receptors (ER), suggesting the potential use of hybrid molecules to target histone methylation and therefore to regulate/redirect hormone receptor signaling.   Here, we report on the action of a pan-KDM inhibitor (3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition.   The 3324 hybrid molecule displays unique features not exhibited by moieties and well-characterized single inhibitors. The compound efficiently inhibits LSD1 as well as UTX enzymes, inducing significant growth arrest and apoptosis in hormone-responsive cells accompanied by a robust increase in H3K4me2 and H3K27me3. Treatment with 3324 reduces the level of ERa in breast and AR in prostate cancer cells at both transcriptional and non-transcriptional levels, acting as a selective endocrine receptor disruptor (SERD). Treatment with 3324 alters the methylation status of ER-regulated promoter regions, thereby affecting the transcription of genes involved in cell surveillance, death, and immune response. 3324 reduces cell proliferation in ex vivo breast cancers by interfering with hormone receptor signaling and/or receptor stability, as well as in cell models with acquired resistance to endocrine therapies (BT474, C4-2 and C4-2b). Similarly, 3324 displays tumor-selective potential in vivo, in both xenograft and chicken embryo models, with no toxicity and good oral efficacy.   This multi-target approach may overcome potential mechanism(s) of resistance caused in part by redundancy and robustness of biological pathways, and find potential application in the treatment of resistant-to-therapy cancers such as those with acquired tamoxifen/enzalutamide resistance. Overall design: Examine expression changes between control and pan-KDM inhibitor 3324 treated MCF7 cells