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BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins

ABSTRACT: Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140488 | GEO | 2019/11/16

REPOSITORIES: GEO

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BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins

Project description:Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.

2020-05-27 | PXD016172 | Pride

The specific interactions of Bcl9/Bcl9L with b-catenin and Pygopus promote breast cancer growth, invasion and metastasis

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

Mouse ameloblasts Bcl9 interactors

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

BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

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

BCL9/9L-Î²-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer

Project description:Canonical Wnt signaling output is mediated by Î²-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-Î²-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-Î²-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-Î²-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-Î²-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

ChIP-seq experiment of the beta-catenin co-factor Bcl9 in developing forelimbs.

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

miR-30-5p functions as a tumor suppressor by targeting BCL9

Project description:Deregulated Wnt/b-catenin signaling underlies the pathogenesis of a broad range of human cancers including multiple myeloma (MM). Thus, the b-catenin transcriptional complex has emerged as a high-priority pharmacologic target. The BCL9 oncogene is a critical transcriptional co-activator of b-catenin, and studies from our laboratory have implicated this transcriptional complex in MM disease initiation and progression. Micro RNAs regulate the expression of oncogenes and tumor suppressor genes, and because they play important roles as biologic inhibitors of cancer growth, they have great potential as novel therapeutic agents. Here we provide evidence for a role of miR-30s family in regulating expression of BCL9 and as a novel therapeutic agent in MM.

2016-08-31 | GSE50422 | GEO

Pull down of full length and mutant BCL9 (deltaHD1) in mouse colorectal tumors and colonic epithelium

Project description:Bcl9 and Bcl9l (Bcl9l) are commonly thought as beta-catenin-dependent Wnt signaling transcriptional activators. Here we searched for BCL9 interacts that could explain the PYGO-independent phenotype induced be the loss of the HD1 (PYGO-binding) domain of BCL9

2020-08-10 | PXD018805 | Pride

Targeted disruption of the BCL9/beta-catenin complex in cancer

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

RNA-seq experiment of developing mouse forelimbs, comparing Bcl9/9l mutant with control littermates.

Project description:Forelimbs were manually dissected from three individual Bcl9/9l-deltaHD1/deltaHD2 mutants and three control littermates, at 10.5 days post coitum. BCL9 and BCL9L are paralogous beta-catenin cofactors involved in the transcriptional machinery of Wnt target genes.

2020-05-08 | E-MTAB-9000 | biostudies-arrayexpress

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