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BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells

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BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells Published OnlineFirst September 8, 2009; DOI: 10.1158/0008-5472.CAN-09-0773 Published Online First on September 8, 2009 as 10.1158/0008-5472.CAN-09-0773 Cell, Tumor, and Stem Cell Biology BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells Mala Mani,1 Daniel E. Carrasco,1 Yunyu Zhang,1 Kohichi Takada,1 Moshe E. Gatt,1 Jui Dutta-Simmons,1 Hiroshi Ikeda,1 Felipe Diaz-Griffero,3 Victor Pena-Cruz,1 Monica Bertagnolli,4 Lois L. Myeroff,6 Sanford D. Markowitz,6,7 Kenneth C. Anderson,1,2 and Daniel R. Carrasco1,5 1Department of Medical Oncology and 2Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School; 3Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School; 4Division of Surgical Oncology and 5Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts; 6Department of Medicine, Case Western Reserve University Medical School and 7Howard Hughes Medical Institute, Cleveland, Ohio Abstract dissociated and the unphosphorylated active h-catenin trans- Several components of the Wnt signaling cascade have been locates to the nucleus, where it functions as a transcriptional shown to function either as tumor suppressor proteins or as activator to activate the expression of target genes, such as c-Myc and cyclin D1 (4, 5). oncogenes in multiple human cancers, underscoring the h relevance of this pathway in oncogenesis and the need for Dysregulation of the canonical Wnt/ -catenin pathway has been further investigation of Wnt signaling components as poten- implicated in numerous human malignancies, generating immense tial targets for cancer therapy. Here, using expression interest in these molecules as targets for cancer therapy (6). The h profiling analysis as well as in vitro and in vivo functional molecular genetics underlying Wnt/ -catenin activation in cancer h studies, we show that the Wnt pathway component BCL9is a centers on mutations that enable -catenin to escape the novel oncogene that is aberrantly expressed in human destruction complex and accumulate in the nucleus. Loss-of- multiple myeloma as well as colon carcinoma. We show that function mutations in the tumor suppressors adenomatous BCL9enhances B-catenin–mediated transcriptional activity polyposis coli and Axin, as well as activating mutations in h regardless of the mutational status of the Wnt signaling -catenin, have been identified in several human cancers including components and increases cell proliferation, migration, colon carcinomas (6, 7). In addition to these defined mutations, h invasion, and the metastatic potential of tumor cells by accumulation of nuclear -catenin has been shown in multiple promoting loss of epithelial and gain of mesenchymal-like myeloma, which lacks known mutations of the Wnt pathway genes, h phenotype. Most importantly, BCL9knockdown significantly indicating alternate pathways for -catenin activation (8–10). Two increased the survival of xenograft mouse models of cancer by recently identified nuclear Wnt pathway components, BCL9 and reducing tumor load, metastasis, and host angiogenesis Pygopus, have been shown to play an important role in h through down-regulation of c-Myc, cyclin D1, CD44, and transcriptional activity of -catenin in association with LEF/TCF vascular endothelial growth factor expression by tumor cells. family members (11). The BCL9 gene resides on chromosome 1q21, Together, these findings suggest that deregulation of BCL9is a region frequently involved in secondary chromosomal abnormal- an important contributing factor to tumor progression. The ities and associated with poor clinical outcome as well as pleiotropic roles of BCL9reported in this study underscore its overexpression of resident genes (12, 13). BCL9 was identified as value as a drug target for therapeutic intervention in several a gene overexpressed in a B-cell acute lymphoblastic leukemia cell malignancies associated with aberrant Wnt signaling. [Cancer line with t(1;14)(q21;q32) translocation (14). In addition, BCL9 has Res 2009;69(19):OF1–10] recently been shown to possess a potent transcription activation domain (15, 16). Taken together, these findings suggest that BCL9 might behave as an oncogene by providing an alternate pathway Introduction for h-catenin activation and subsequent tumor progression. The Wnt pathway consists of a highly conserved and tightly Here, we provide evidence that BCL9 deregulation is one regulated receptor-mediated signal transduction system (1–3). such alternate mechanism of activation. Regardless of the Association of Wnt ligands with Frizzled and low-density mutational status of the Wnt signaling components, BCL9 lipoprotein receptor–related protein (LRP5 and LRP6) coreceptors enhanced h-catenin–mediated transcriptional activity in cancers leads to stabilization of h-catenin, a key event in this signal with (colon carcinoma) and without (multiple myeloma) Wnt/ transduction pathway. In the absence of Wnt signal, h-catenin is h-catenin activating mutations. BCL9 is overexpressed in a subset phosphorylated by a destruction complex consisting of adenoma- of multiple myeloma and colon carcinoma primary tumors as well tous polyposis coli, Axin, glycogen synthase kinase-3h, and casein as cell lines. BCL9 enhanced proliferation, survival, migration, kinase 1a, marking it for ubiquitination and proteasome degrada- invasion, and the metastatic potential of tumor cells. In addition, tion. In the presence of Wnt ligands, this destruction complex is BCL9 knockdown enhanced the survival of xenograft mouse models of cancer and attenuated the expression of CD44 and vascular endothelial growth factor (VEGF) secretion by tumor cells, Note: Supplementary data for this article are available at Cancer Research Online thereby reducing tumor metastasis and host angiogenesis. We (http://cancerres.aacrjournals.org/). Requests for reprints: Daniel R. Carrasco, Dana-Farber Cancer Institute, 44 Binney provide evidence for the involvement of BCL9 in the progression of Street, Dana 530C, Boston, MA 02115. Phone: 617-582-8159; Fax: 617-582-8160; E-mail: these malignancies by favoring an epithelial-to-mesenchymal [email protected]. I2009 American Association for Cancer Research. transition (EMT)–like differentiation of tumor cells. These data doi:10.1158/0008-5472.CAN-09-0773 confirm that BCL9 is involved in tumor progression, underscoring www.aacrjournals.org OF1 Cancer Res 2009; 69: (19). October 1, 2009 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst September 8, 2009; DOI: 10.1158/0008-5472.CAN-09-0773 Cancer Research its relevance as a novel therapeutic target in cancers associated Quantitative reverse transcription-PCR. RNA was extracted with Trizol with dysregulated Wnt activity. reagent (Invitrogen) according to the manufacturer’s protocol. cDNA synthesis was done with 2 Ag RNA for each sample using SuperScript VILO cDNA synthesis kit (Invitrogen) according to the manufacturer’s instructions. Materials and Methods Quantitative reverse transcription-PCR was carried out using Eppendorf Mastercycler realplex2 and analysis of target genes was done in triplicates Cell lines. Plasma cells and multiple myeloma cell lines were collected using the SYBR Green quantitative PCR master mix (Fermentas) with the and maintained as described (8). Colon cancer cell lines were obtained from designated forward and reverse primers: BCL9 (CCAACTTGCCATCAATGAA- the American Type Culture Collection and the German Collection of TAA and GGCATCTGATTGGAGTGAGAA), c-Myc (TTTTTCGGGTAGTG- Microorganisms and Cell Cultures. Control and Wnt3A conditional media GAAAACC and GCAGTAGAAATACGGCTGCAC), cyclin D1 (5TGTCCTACTA- were collected from supernatants of L cells (CRL-2648) and L-Wnt3A cells CCGCCTCACAC and TGGGGTCCATGTTCTGCT), CD44 (TTTGCATTGCA- (CRL-2647) were from the American Type Culture Collection. GTCAACAGTC and TGAGTCCACTTGGCTTTCTGT), and VEGF (CAT- Expression profiling. Affymetrix GeneChip for multiple myeloma GAACTTTCTGCTGTCTTGG and ATGATTCTGCCCTCCTCCTT). Gene ex- primary tumors, cell lines, and normal plasma cells was obtained from pression values were calculated relative to h-actin expression for each sample. the National Center for Biotechnology Information Gene Expression Immunoblotting analysis. Immunoblot analysis was done as described Omnibus.8 RNA from colon carcinoma primary tumors, cell lines, and previously (8) using antibodies against BCL9 (6109), h-catenin (CAT5-H10; normal cells were run on Affymetrix Human Exon 1.0 ST Array. RNA from Zymed), c-Myc (OP10; Calbiochem), BCL9 (ab37305; Abcam), BCL9 peptide MM1S and Colo320 control shRNA or BCL9 shRNA cells were run on an (ab37304; Abcam), glyceraldehyde-3-phosphate dehydrogenase (ab9485; Affymetrix U133A 2.0 array chip as described (8). Statistical analyses were Abcam), and IgE (DB2001; DeltaBiolabs). Antibodies against GFP (B-2), done in R9 using Bioconductor software (17). Probe-set expression values FLAG-M2, actin-horseradish peroxidase (C-11), and cyclin D1 (H-295) and were generated using ‘‘plier.’’10 Moderated t test was applied and a P-value secondary antibodies conjugated to horseradish peroxidase were from cutoff of 0.05 after multiple testing adjustments with BH method was used Santa Cruz Biotechnology and Southern Biotechnology. (18). Immunofluorescence analysis. Cell samples were prepared using a
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