The BCL6 proto-oncogene encodes a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation, and survival. BCL6 suppresses p53 in GCB-cells and its constitutive expression can protect B-cell lines from apoptosis induced by DNA damage. BCL6-mediated expression may allow GCB-cells to sustain the low levels of physiological DNA breaks related to somatic mutation (SM) and immunoglobulin class switch recombination which physiologically occur in GCB-cells. Three types of genetic events occur in the BCL6 locus and involve invariably the 5' non-coding region and include translocations, deletions and SM actively targeted to the 5' untranslated region. These acquired mutations occur independently of translocations but may be involved in the deregulation of the gene and/or translocation mechanisms. The favorable prognostic value of high levels of BCL6 gene expression in NHL seems well-established. By contrast, the relevance of SM or translocation of the gene remains unclear. However, it is likely that non-Hodgkin's lymphomas (NHL) harboring the most frequent translocation involving BCL6, i.e. t(3;14), are characterized by a common cell of origin and similar oncogenic mechanisms. Several experiments and mouse models mimicking BCL6 translocation occurring in human lymphoma have demonstrated the oncogenic role of BCL6 and constitute a rational to consider BCL6 as a new therapeutic target in NHL. BCL6 blockade can be achieved by different strategies which include siRNA, interference by specific peptides or regulation of BCL6 acetylation by pharmacological agents such as SAHA or niacinamide and would be applicable to most type of B-cell NHL.
"The acetylation status of STAT5, as modulated by p300 and HDACs, is a critical determinant of its activity (Icardi et al., 2012; Rascle et al., 2003). The HDACs have often been implicated in transcriptional repression (Fischle et al., 2001; Icardi et al., 2012; Narlikar et al., 2002), and multiple Class I and Class II HDACs associate with BCL6 (Jardin et al., 2007). HDAC3 is a Class I HDAC which plays a prominent role in regulation of genes mediating adipocyte metabolism and adipogenesis (Alenghat et al., 2008; Feng et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Expression of the Growth Hormone (GH)-stimulated gene Socs2 (Suppressor Of Cytokine Signaling 2) is mediated by the transcription activator STAT5 (Signal Transducer and Activator of Transcription 5) and the transcription repressor BCL6 (B-cell lymphoma 6). ChIP-Sequencing identified Cish (Cytokine-inducible SH2-containing protein) and Bcl6 as having similar patterns of reciprocal occupancy by BCL6 and STAT5 in response to GH, though GH stimulates Cish and inhibits Bcl6 expression. The co-activator p300 occupied Socs2, Cish and Bcl6 promoters, and enhanced STAT5-mediated activation of Socs2 and Cish. In contrast, on Bcl6, p300 functioned as a repressor and inhibited in conjunction with STAT5 or BCL6. The co-repressor HDAC3 (Histone deacetylase 3) inhibited the Socs2, Cish and Bcl6 promoters in the presence of STAT5. Thus transcriptional outcomes on GH-regulated genes occupied by BCL6 and STAT5 are determined in a promoter-specific fashion by co-regulatory proteins which mediate the distinction between activating and repressive transcription factors.
"To this end, human B-cell lymphoma 6 (BCL6) is a 95 kDa nuclear protein, belonging to the BTB/POZ (BR-C, ttk and bab/Pox virus and Zinc finger) domain family of transcription factors. BCL6 protein has been reported as a master regulator of B lymphocyte development and growth [3,4] and altered BCL6 protein expression was implicated in pathogenesis of diverse human hematologic malignancies, especially in the diffuse large B cell lymphoma (DLBCL), the most common lymphoma in adults [5-7]. Overexpression of BCL6 was frequently shown in DLBCL patients due to a functional mutation in the BCL6 promoter . "
[Show abstract][Hide abstract] ABSTRACT: Background
B-cell lymphoma 6 (BCL6) protein, an evolutionarily conserved zinc finger transcription factor, showed to be highly expressed in various human cancers in addition to malignancies in the lymphoid system. This study investigated the role of BCL6 expression in breast cancer and its clinical significance in breast cancer patients.
Expression of BCL6 protein was assessed using in situ hybridization and immunohistochemistry in 127 breast cancer patients and 50 patients with breast benign disease as well as in breast cell lines. Expression of BCL6 was restored or knocked down in two breast cancer cell lines (MCF-7 and T47D) using BCL6 cDNA and siRNA, respectively. The phenotypic change of these breast cancer cell lines was assessed using cell viability MTT, Transwell invasion, colony formation, and flow cytometry assays and in a xenograft mice model. Luciferase reporter gene, immunoblot, and qRT-PCR were used to investigate the molecular events after manipulated BCL6 expression in breast cancer cells.
BCL6 protein was highly expressed in breast cancer cell lines and tissue specimens and expression of BCL6 protein was associated with disease progression and poor survival of breast cancer patients. In vitro, the forced expression of BCL6 results in increased proliferation, anchorage-independent growth, migration, invasion and survival of breast cancer cell lines, whereas knockdown of BCL6 expression reduced these oncogenic properties of breast cancer cells. Moreover, forced expression of BCL6 increased tumor growth and invasiveness in a nude mouse xenograft model. At the gene level, BCL6 was a target gene of miR-339-5p. Expression of BCL6 induced expression of CXCR4 and cyclinD1 proteins.
The current study demonstrated the oncogenic property of BCL6 in breast cancer and further study could target BCL6 as a novel potential therapeutic strategy for breast cancer.
BMC Cancer 06/2014; 14(1):418. DOI:10.1186/1471-2407-14-418 · 3.36 Impact Factor
"BCL-6 (B-cell lymphoma 6) was originally identified in translocations of non-Hodgkin’s lymphomas and was subsequently characterized as a potent transcriptional repressor with immunoregulatory function in germinal center development, memory T-cell generation and chemokine expression . Its activity in endothelial cells (ECs) was reported to involve PPARδ (peroxisome proliferator-activated receptor delta) regulation in the context of inflammation . "
[Show abstract][Hide abstract] ABSTRACT: Nuclear inclusions of aggregated proteins have primarily been characterized for molecules with aberrant poly-glutamine repeats and for mutated or structurally altered proteins. They were termed "nuclear aggresomes" and misfolding was shown to promote association with molecular chaperones and proteasomes. Here, we report that two components of a transcriptional repressor complex (BCL-6 and BCoR) of wildtype amino acid sequence can independently or jointly induce the formation of nuclear aggregates when overexpressed. The observation that the majority of cells rapidly downregulate BCL-6/BCoR levels, supports the notion that expression of these proteins is under tight control. The inclusions occur when BCL-6/BCoR expression exceeds 150-fold of endogenous levels. They preferentially develop in the nucleus by a gradual increase in aggregate size to form large, spheroid structures which are not associated with heat shock proteins or marked by ubiquitin. In contrast, we find the close association of BCL-6/BCoR inclusions with PML bodies and a reduction in aggregation upon the concomitant overexpression of histone deacetylases or heat shock protein 70. In summary, our data offer a perspective on nuclear aggregates distinct from classical "nuclear aggresomes": Large complexes of spheroid structure can evolve in the nucleus without being marked by the cellular machinery for protein refolding and degradation. However, nuclear proteostasis can be restored by balancing the levels of chaperones.
PLoS ONE 10/2013; 8(10):e76845. DOI:10.1371/journal.pone.0076845 · 3.23 Impact Factor
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