Abstract
Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (−87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis.
Highlights
Lipopolysaccharide-induced Tumor necrosis factor (TNF)-alpha factor (LITAF), encoding a transcription factor, was initially identified as the p53- inducible gene7 in 1997 [1]
To explore the biological functions of Lipopolysaccharide-induced TNF-alpha factor (LITAF) in B cells, we detected the expression of LITAF and B-cell CLL/lymphoma 6 (BCL6) in 55 B-NHL samples by immunochemistry (Table 1)
We found that co-transfection of LITAF and BCL6 in 293T cells induced an interaction (Figure 3B), which reveal the existence of a protein-protein interaction between the two transcription factors in vivo
Summary
LITAF, encoding a transcription factor, was initially identified as the p53- inducible gene (termed Pig7) in 1997 [1]. Subsequent studies have demonstrated that LITAF could bind to a sequence motif, CTCCC (-515 to -511), within the TNF promoter, activating transcription of TNF upon lipopolysaccharide (LPS) stimulation [2, 3]. Apart from its critical role in inflammatory response, mutations in LITAF are associated with Paget’s disease [4] and CharcotMarie-Tooth disease (CMT) [5, 6]. Accumulating evidences have indicated that LITAF may be considered as a tumor suppressor in different malignancies. LITAF was identified to promote cell apoptosis and differentiation in acute myeloid leukaemia [8], and the decreased expression was observed in breast cancer [9]
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