title: The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma.
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.
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.|Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yaoyao
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Kuai
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Lei
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Weng
authors.affiliation: Institute of Pathology, Wuerzburg University, Wuerzburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Berberich-Siebelt
authors.affiliation: Epitomics Inc., Hangzhou, China.
authors.forename: Xinxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Hangzhou First People's Hospital, Hangzhou, China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Postgraduate School in Medical School of Ningbo University, Ningbo, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Ren
authors.affiliation: Epitomics Inc., Hangzhou, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Pathology and Pathophysiology, Institute of Pathology and Forensic Medicine, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C118738:LITAF protein, human; D009687:Nuclear Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors
keywords: B-NHL; BCL6; LITAF; apoptosis; transcription