Targeted disruption of the BCL9/beta-catenin complex in cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE33143 | GEO | 2012/08/23
SECONDARY ACCESSION(S): PRJNA149393
REPOSITORIES: GEO
Similar Datasets
Project description:Stabilized Alpha-Helix peptides of BCL9 HD2 (SAH-BCL9) block BCL9 and B9L interactions with beta-catenin and specifically downregulate Wnt target gene expression. RNA from triplicate SAH-BCL9B- and vehicle-treated DLD1 samples (10 µM each for 12 hours) was hybridized to Affymetrix Human U133 Plus 2.0 arrays to asses global gene expression changes.
2012-08-23 | E-GEOD-33143 | biostudies-arrayexpress
Project description:Summary: We studied how the binding of beta-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with beta-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of beta-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the effect of disrupting the HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus was more moderate. Interfering with the beta-catenin - Bcl9/Bcl9L - Pygo chain of adaptors only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGF-beta treatment. The results indicate that Bcl9/Bcl9L critically enforce canonical Wnt signaling in its contribution to breast cancer growth and malignant progression.
2021-08-20 | GSE182404 | GEO
Project description:We isolated ca. 500 forelimbs at 10 days post coitum, and performed ChIP-seq using anti-Bcl9 antibodies. Bcl9 is a beta-catenin transcriptional cofactor, therefore it allows the identification of binding sites of the canonical Wnt signalling-dependent transcriptional complex. This experiment allowed to define that, in this developmental context, Bcl9 acts as a beta-catenin dedicated partner. Moreover, it established a series of genome-wide Bcl9 (therefore Wnt/beta-catenin) tissue-specific target loci, thereby assessing the genetic relationship existing between Wnt signaling and other signalling cascades (e.g. the Bmp pathway).
2019-02-21 | E-MTAB-7652 | biostudies-arrayexpress
Project description:Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome.
2015-11-08 | GSE60837 | GEO
Project description:Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome. Examination of Bcl9/9l-knockout versus wild-type transcriptome in murine AOM-DSS tumors, APC-Kras tumors and healthy colocyte extracts.
2015-11-08 | E-GEOD-60837 | biostudies-arrayexpress
Project description:Bcl9 and Bcl9l (Bcl9l) are commonly thought as beta-catenin-dependent Wnt signaling transcriptional activators. We find however that, in the enamel-producin ameloblasts cells, Bcl9/9l are localiyed in the cytoplasm toward to apical secretory membrane. We performed pull down followed by mass spectrometry analysis to discover the molecular partners of Bcl9 that could explain this cytoplasmic localyzation.
2017-02-13 | PXD005449 | Pride
Project description:HCT116 colorectal cancer cells were treated with a novel inhibitor of ß-catenin/BCL9 interaction and evaluated for transcriptional changes using RNA-seq.
2022-01-01 | GSE182086 | GEO
Project description:There is limited research on which specific Wnt targets are regulated by B-Cell Lymphoma-9 (BCL9) and whether BCL9 regulates other signaling pathways to drive cancer malignancy. Here we demonstrated that BCL9 drives DCIS invasive progression by regulation of genes involved in cellular growth, invasion and migration.
2020-01-17 | GSE143790 | GEO
Project description:About 500 forelimbs were isolated at 10.5 days post coitum, and ChIP-seq was performed using anti-BCL9 (Abcam, ab37305) and anti-TBX3 (Santacruz, sc17871) antibodies. BCL9 is a beta-catenin transcriptional cofactor involved in the transcriptional machinery of Wnt target genes. TBX3 is a transcription factor important in limb development. This experiment identified, in this developmental context, co-occupancy of BCL9 and TBX3 on a genome-wide scale, and at Wnt-related loci, suggesting co-operation between these transcription factors in Wnt-driven limb development (Zimmerli et al. in revision during spring 2020). The following files are available for this experiment: - Raw sequencing data (.fastq) - Genomic enrichment data in bedgraph format (.bdg) which can be used for visualization in a genome browser. - Annotated peak files (.txt) containing high confidence peaks with genomic annotation. NOTE: The raw data relative to the BCL9 ChIP were previously deposited under accession number E-MTAB-7652, and described in Salazar et al. 2019. For simplicity, and to allow easy retrieval, we add the raw data of the entire experiment (including also BCL9) along with the newly generated analyses.
2020-05-08 | E-MTAB-8997 | biostudies-arrayexpress
Project description:Deregulated Wnt/?-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of ?-catenin with B cell lymphoma 9 (BCL9), a co-activator for ?-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives ?-catenin signaling through direct binding mediated by its ?-helical homology domain 2. We developed a stabilized ? helix of BCL9 (SAH-BCL9), which we show targets ?-catenin, dissociates native ?-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-?-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.
| S-EPMC3631420 | biostudies-literature