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

// Yaoyao Shi 1, 2 , Yue Kuai 1 , Lizhen Lei 1 , Yuanyuan Weng 1 , Friederike Berberich-Siebelt 3 , Xinxia Zhang 4 , Jinjie Wang 5 , Yuan Zhou 6 , Xin Jiang 1 , Guoping Ren 7 , Hongyang Pan 4 , Zhengrong Mao 1 , Ren Zhou 1 1 Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China 2 Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 3 Institute of Pathology, Wuerzburg University, Wuerzburg, Germany 4 Epitomics Inc., Hangzhou, China 5 Department of Pathology, Hangzhou First People’s Hospital, Hangzhou, China 6 Postgraduate School in Medical School of Ningbo University, Ningbo, China 7 Department 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.