Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression lead to leukemogenic transformation. Here, for the first time, we comprehensively prove NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes – HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention.
Bone is the most common site of metastasis from breast cancer, which is the most prevalent cancer affecting women globally. Bone metastasis from breast cancer severely affects the quality of life of patients and increases mortality. The molecular mechanisms of metastasis, colonization, and proliferation of breast cancer cells in bone are complex and involve the interaction between breast cancer cells and the bone microenvironment. However, the precise mechanism is not clear at present. In recent years, the Hippo signaling pathway has attracted much attention due to its important role in regulating the expression of major effector molecules during tumor development. In particular, studies have found that the mutation and aberrant expression of the core components of the Hippo signaling pathway affect breast cancer cell migration and invasion, indicating that this pathway plays a role in bone metastasis, although the molecular mechanism of this pathway in breast cancer metastasis has not been fully elucidated. In this review, we discuss the function of the Hippo signaling pathway, introducing its role in breast cancer metastasis, especially bone metastasis of breast cancer, so as to lay a solid theoretical foundation for further research and for the development of effective targeted therapeutic agents.
Transcription factors (TFs) activate enhancers to drive cell-specific gene expression in response to signals, but our understanding of enhancer assembly in signaling events is incomplete. Here, we show that Androgen Receptor (AR), a steroid hormone-regulated transcription factor, forms condensates through multivalent interactions in response to androgen signaling to orchestrate enhancer assembly. We demonstrate that the intrinsically disordered N-terminal domain (NTD) of AR drives 1,6-Hexanediol-sensitive condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by IDRs from selective proteins for AR condensation capacity and transactivation function. Surprisingly, strengthened AR condensation capacity caused by extending the polyQ tract within AR NTD also leads to impaired transcriptional activity without affecting AR binding on enhancers. Furthermore, either NTD deletion or polyQ extension reduces heterotypic multivalent interactions between AR and other enhancer components. These results suggest the importance of an optimal level of AR condensation in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate enhancer assembly in response to signals. Our study supports that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies, therefore providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions.
<p>Supplementary Figure S1 is associated with Figure1 and it shows the NPM1-WT binds to the rDNA arrays and NPM1c binds to non-repetitive genomic regions. Supplementary Figure S2 is associated with Figure1 and it shows NPM1c’s chromatin binding and association with gene expression. Supplementary Figure S3 is associated with Figure2 and shows NPM1c regulates the transcription of its target genes with BRU-seq. Supplementary Figure S4 is associated with Figure2 and it shows the characterization of NPM1c condensate with biochemical assay and imaging assay. Supplementary Figure S5 is associated with figure 3. The figure shows NPM1c and chromatin landacpe dymanics during dTag-13 treatment and wash-off. Supplementary Figure S6 is associated with figure 4. It shows the supplemental data of HOXB8-NPM1c-knock-in model. Supplementary figure S7 is associated with figure 5. It shows the supplemental data of XPO1's binding to chromatin in various leukemia cell lines and normal HSPCs. Supplementary Figure S8 is associated with figure 6. It shows the supplemental information of synergy between Menin and XPO1 inhibitor in the NPM1c AML cell line model.</p>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.