FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas

Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature (Impact Factor: 41.46). 11/2011; 481(7379):90-3. DOI: 10.1038/nature10688
Source: PubMed


BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease. In many DLBCL patients, BCL6 overexpression is achieved through translocation (~40%) or hypermutation of its promoter (~15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5, 6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.

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    • "Deletion or mutation of FBXO11 was found in ∼20% of DLBCL patients, indicating that FBXO11 is a tumor suppressor in DLBCL. Oncoprotein BCL6, whose upregulation drives DLBCL development, was identified as a substrate of FBXO11 for SCF-mediated degradation [9]. Besides, FBXO11 mutations were observed in colon cancer, lung cancer, ovarian cancer, head and neck squamous cell carcinoma , as well as Burkitt lymphoma, implying that FBXO11 may act as a tumor suppressor in several cancers [5]. "
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    ABSTRACT: MicroRNAs (miRNAs) are small endogenous non-coding RNAs, which play critical roles in cancer development by suppressing gene expression at the post-transcriptional level. In general, oncogenic miRNAs are upregulated in cancer, while miRNAs that act as tumor suppressors are downregulated, leading to decreased expression of tumor suppressors and upregulated oncogene expression, respectively. F-box proteins function as the substrate-recognition components of the SKP1-CUL1-F-box (SCF)-ubiquitin ligase complex for the degradation of their protein targets by the ubiquitin-proteasome system. Therefore F-box proteins and miRNAs both negatively regulate target gene expression post-transcriptionally. Since each miRNA is capable of fine-tuning the expression of multiple target genes, multiple F-box proteins may be suppressed by the same miRNA. Meanwhile, one F-box proteins could be regulated by several miRNAs in different cancer types. In this review, we will focus on miRNA-mediated downregulation of various F-box proteins, the resulting stabilization of F-box protein substrates and the impact of these processes on human malignancies. We provide insight into how the miRNA: F-box protein axis may regulate cancer progression and metastasis. We also consider the broader role of F-box proteins in the regulation of pathways that are independent of the ubiquitin ligase complex and how that impacts on oncogenesis. The area of miRNAs and the F-box proteins that they regulate in cancer is an emerging field and will inform new strategies in cancer treatment.
    Seminars in Cancer Biology 10/2015; DOI:10.1016/j.semcancer.2015.09.016 · 9.33 Impact Factor
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    • "The oncogenic protein BCL6 forms the primary target of FBXO11 [44] and it has been observed that the knockdown of FBXO11 in C. elegans as well is in mice to be lethal [45] [46]. Deletion of FBXO11 gene in DLBCL cell line increased the expression of BCL6 while, the reconstitution resulted in low BCL6 expression via ubiquitination which in turn inhibited cell proliferation and induced apoptotic cell death [47]. Recently, FBXO11 has been found to reverse epithelialto-mesenchymal transition (EMT) through Ser-11 phosphorylation on SNAIL by protein kinase D1 (PKD1) [48] suggesting that PKD1- FBXO11-SNAIL axis together regulate EMT and cancer metastasis. "
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    ABSTRACT: The Ubiquitin Proteasome System (UPS) is a core regulator with various protein components (ubiquitin-activating E1 enzymes, ubiquitin-conjugating E2 enzymes, ubiquitin-protein E3 ligases, and the 26S proteasome) which work together in a coordinated fashion to ensure the appropriate and efficient proteolysis of target substrates. E3 ubiquitin ligases are essential components of the UPS machinery, working with E1 and E2 enzymes to bind substrates and assist the transport of ubiquitin molecules onto the target protein. As the UPS controls the degradation of several oncogenes and tumor suppressors, dysregulation of this pathway leads to several human malignancies. A major category of E3 Ub ligases, the SCF (Skp-Cullin-F-box) complex, is composed of four principal components: Skp1, Cul1/Cdc53, Roc1/Rbx1/Hrt1, and an F-box protein (FBP). FBPs are the substrate recognition components of SCF complexes and function as adaptors that bring substrates into physical proximity with the rest of the SCF. Besides acting as a component of SCF complexes, FBPs are involved in DNA replication, transcription, cell differentiation and cell death. This review will highlight the recent literature on three well characterized FBPs SKP2, Fbw7, and beta-TRCP. In particular, we will focus on the involvement of these deregulated FBPs in the progression and development of various human cancers. We will also highlight some novel substrates recently identified for these FBPs.
    Seminars in Cancer Biology 09/2015; DOI:10.1016/j.semcancer.2015.09.008 · 9.33 Impact Factor
    • "Our results identify FBXO11 as an important miR-21 target gene. In addition, there was an inverse relationship between FBXO11 and BCL6 expression in various human cancer cell lines, and FBXO11 overexpression resulted in markedly lower BCL6 levels, which is consistent with the finding that FBXO11 directly mediates BCL6 degradation [Duan et al., 2012]. Although the role of BCL6 in lymphoma is fairly well defined [Parekh et al., 2007], these findings suggest that BCL6 may also play an important role in non-lymphoid cancers as well. "
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    ABSTRACT: Preclinical Research MicroRNAs (miRNAs) are small endogenous noncoding RNAs that suppress gene expression at the post-transcriptional level. In the past decade, miRNAs have been extensively studied in a number of different human cancers. MiRNAs have been identified to act both as oncogenes and as tumor suppressors. In addition, miRNAs are associated with the intrinsic resistance of cancer to various forms of therapy, and they are implicated in both tumor progression and metastasis. The characterization of the specific alterations in the patterns of miRNA expression in cancer has great potential for identifying biomarkers for early cancer detection, as well as for potential therapeutic intervention in cancer treatment. In this chapter, we describe the ever-expanding role of miR-21 and its target genes in different cancers, and provide insight into how this oncogenic miRNA regulates cancer cell proliferation, migration, and apoptosis by suppressing the expression of tumor suppressors. Drug Dev Res, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Drug Development Research 06/2015; 76(6):n/a-n/a. DOI:10.1002/ddr.21257 · 0.77 Impact Factor
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