Oncotarget

Research Papers:

The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin’s-lymphoma

Yaoyao Shi, Yue Kuai, Lizhen Lei, Yuanyuan Weng, Friederike Berberich-Siebelt, Xinxia Zhang, Jinjie Wang, Yuan Zhou, Xin Jiang, Guoping Ren, Hongyang Pan, Zhengrong Mao and Ren Zhou _

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Oncotarget. 2016; 7:77444-77456. https://doi.org/10.18632/oncotarget.12680

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Abstract

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

Correspondence to:

Ren Zhou, email: zhouren@zju.edu.cn

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

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.


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