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Inhibition of PRC1.1 augments Wnt signaling to promote bone remodeling

ABSTRACT: The Wnt/β-catenin signaling play critical roles in bone formation and homeostasis. However, chromatin regulatory mechanisms governing transcriptional response to the signaling are poorly understood. Polycomb group proteins are conserved epigenetic repressors safeguarding cell identity and functions, through forming multi-subunit complexes (PRCs). Their activities on histone modifications relies on interaction with the core enzyme, providing basis for therapeutic intervention. Here in aging osteoblasts, we observed a selective gain of PRC1.1 function, with KDM2B serving as a chromatin binding factor while BCOR and PCGF1 as key catalytically accessory proteins for histone H2A monoubiquitylation (H2AK119ub1). Using genetic models, we found that osteoblast-specific KDM2B inactivation significantly improves bone structure and density under steady-state conditions or scenarios of bone loss, such as aging, estrogen deficiency (following ovariectomy), or acute trauma. This improvement is attributed to the activation Wnt signaling. Transcriptomic and epigenomic analyses in purified osteoblasts demonstrate that KDM2B inactivation results in decreased H2AK119ub1 levels at the promoters of Wnt/β-catenin target genes, leading to their derepression. Through virtual screening and experimental validation, we identified a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Importantly, this inhibitor enhances bone formation in mouse models with bone loss. Therefore, our findings suggest that targeting PRC1.1 strengthens cellular response to Wnt signaling and may offer a promising strategy to combat bone deterioration.

ORGANISM(S): Mus musculus

PROVIDER: GSE280429 | GEO | 2025/04/24

REPOSITORIES: GEO

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Project description:Inhibitors of Wnt signaling have been previously shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts (OBSOSTKO) promotes PC invasion while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells as quantified by TOPFLASH reporter and b-catenin activity, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts up-regulated under highly invasive conditions. Following further analysis we found that CRIM1 increases PC3 invasion, complexes with b-catenin, and promotes cell-adhesion, suggesting that elevated Wnt signaling secreted from the bone may promote PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of metastatic cancer cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via tail vein did not readily metastasize in NSG xenografts, suggesting that targeting the molecular bone environment may influence bone metastatic outcome in clinical settings. PC3 cells were cultured for 48 hours in specified conditions prior to RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 Array. All experiments were performed in at least duplicates. Total RNA was collected from PC3 cells cultured in normal growth media, cocultured with WT mouse osteoblasts supplemented with recombinant human DKK1, cells cocultured with WT mouse osteoblasts supplemented with recombinant human SOST, or cocultured with SostKO mouse osteoblasts.

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Inhibition of PRC1.1 augments Wnt signaling to promote bone remodeling

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