GSE119702
Effect of Fbxo22 on ER and SRC-3 recruitment to the genomic loci
The 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 Receptor Type 2 (HER-2)-negative breast cancers with high hazard ratios independently of other markers such as Ki-67 and node status. We propose that the level of Fbxo22 in tumor tissues defines a new subclass of ER-positive breast cancers for which patients SCFFbxo22-mediated KDM4B degradation can be a therapeutic target by the next generation of SERMs. We carried out the analysis using MCF-7 and Fbxo22-depleted MCF-7 cells. Cells were estrogen-starved for 72 hrs and subsequently stimulated for 2 hrs by E2 (10 nM) or E2 plus TAM. As a result, we identified a total of 12,645 and 23,216 enriched ER peaks in MCF-7 and Fbxo22-depleted MCF-7cells, respectively, in cells treated with E2, and 26,751 and 19,924 enriched ER peaks in MCF-7 and Fbxo22-depleted MCF-7cells, respectively, in cells treated with E2 plus 4-OHT. Overall design: Examination of ER and SRC-3 in control or shFbxo22 MCF7 cells