GSE119702 Effect of Fbxo22 on ER and SRC-3 recruitment to the genomic loci

Contributors : Yoshikazu Johmura ; Makoto NakanishiSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensThe agonistic/antagonistic bio-character of selective estrogen receptor modulators (SERMs) can have therapeutic advantages, particularly in the case of premenopausal breast cancers. Although the contradictory effects of these modulators have been studied in terms of cross-talk between estrogen receptor (ER)-coactivator dynamics and growth factor signaling, the molecular basis of these mechanisms is still obscure. We demonstrate here an unidentified series of regulatory mechanisms controlling cofactor dynamics on ER and SERM function whose activities require F-box protein 22 (Fbxo22). Skp, Cullin, F-box containing complex (SCF)Fbxo22 ubiquitylates lysine demethylase 4B (KDM4B) complexed with tamoxifen-bound ER, whose degradation releases steroid receptor coactivator (SRC) from ER. Depletion of Fbxo22 results in ER-dependent transcriptional activation via transactivation function 1 (AF1) function even in the presence of SERMs. In living cells, tamoxifen releases SRC and KDM4B from ER in a Fbxo22-dependent manner. SRC release by tamoxifen requires Fbxo22 on almost all ER-SRC-bound enhancer/promoters. Tamoxifen fails to prevent growth of Fbxo22-depleted ER-positive breast cancers both in vitro and in vivo. Clinically, a low level of Fbxo22 in tumor tissues predicts a poorer outcome in ER-positive/Human Epidermal Growth Factor Re...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Source Type: research