Article

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

ABSTRACT

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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    • "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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    • "TP53 responds to diverse cellular stresses by regulating the expression of specific target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair or metabolic changes (Dai and Gu 2010; Lane 1992). An example of cluster 1 protein is the F-box protein FBOX11, which interacts with the E3 ubiquitin–protein ligase complex that mediates ubiquitination and subsequent proteasomal degradation of target proteins involved in diverse biological process (Duan et al. 2012), which therefore can be predicted to be sensitive to zinc availability . Of the 20 top ZNBPs in cluster 3, twelve are involved in gene expression either directly, as transcription factors (tumor suppressor genes P53, P63, BCL6, SSH, PML, SMAD2, SMAD3, SMAD4, SMAD7), or indirectly, as regulators of the DNA dwelling or DNA repair processes (HDAC4, HDAC5, BRCA1). "
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