The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin’s-lymphoma
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Yaoyao Shi1,2, Yue Kuai1, Lizhen Lei1, Yuanyuan Weng1, Friederike Berberich-Siebelt3, Xinxia Zhang4, Jinjie Wang5, Yuan Zhou6, Xin Jiang1, Guoping Ren7, Hongyang Pan4, Zhengrong Mao1, Ren Zhou1
1Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China
2Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
3Institute of Pathology, Wuerzburg University, Wuerzburg, Germany
4Epitomics Inc., Hangzhou, China
5Department of Pathology, Hangzhou First People’s Hospital, Hangzhou, China
6Postgraduate School in Medical School of Ningbo University, Ningbo, China
7Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Ren Zhou, email: email@example.com
Zhengrong Mao, email: Maozr@zju.edu.cn
Keywords: LITAF, BCL6, transcription, apoptosis, B-NHL
Received: April 13, 2016 Accepted: September 02, 2016 Published: October 15, 2016
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.
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