Transcription factor CCAAT/enhancer-binding protein alpha and critical circadian clock downstream target gene PER2 are highly deregulated in diffuse large B-cell lymphoma

Abstract Disturbances of circadian rhythms and mammalian clock genes have been implicated in the etiologies of many chronic illnesses, including cancer. We show that transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha)-regulated PER2 activation is a potential tumor suppressor pathw...

Full description

Saved in:
Bibliographic Details
Published in:Leukemia & lymphoma 2012-08, Vol.53 (8), p.1577-1585
Main Authors: Thoennissen, Nils H., Thoennissen, Gabriela B., Abbassi, Sam, Nabavi-Nouis, Shayan, Sauer, Tim, Doan, Ngan B., Gery, Sigal, Müller-Tidow, Carsten, Said, Jonathan W., Koeffler, H. Phillip
Format: Article
Language:English
Subjects:
Apoptosis
Biopsy
CCAAT-Enhancer-Binding Protein-alpha - biosynthesis
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cell Survival
Circadian Rhythm
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes, Reporter
Humans
Lymphoma, Large B-Cell, Diffuse - genetics
Lymphoma, Large B-Cell, Diffuse - metabolism
mature B-cell lymphoma
Models, Genetic
Period Circadian Proteins - biosynthesis
Transcription factor
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Disturbances of circadian rhythms and mammalian clock genes have been implicated in the etiologies of many chronic illnesses, including cancer. We show that transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha)-regulated PER2 activation is a potential tumor suppressor pathway in diffuse large B-cell lymphoma (DLBCL), one of the commonest types of mature B-cell lymphoma. Expression analysis of human B-cell lymphoma samples including DLBCL (n = 50), mantle cell (n = 21), follicular (n = 25) and Burkitt (n = 18) lymphoma revealed markedly down-regulated CEBPA and PER2 mRNA levels exclusively in DLBCL samples compared to control lymphatic tissue. We demonstrated direct regulation of the circadian core clock gene PER2 by C/EBPalpha in the pro-B cell line Ba/F3, and forced expression of PER2 resulted in decreased proliferation, G0/G1 cell cycle arrest and increased rates of apoptosis. Interestingly, treatment of human DLBCL cell lines with the histone deacetylase-inhibitor suberoylanilide hydroxamic acid (SAHA) significantly increased the expression of C/EBPalpha and Per2, accompanied by cell growth inhibition; in contrast, siRNA knockdown of CEBPA reduced the anti-proliferative effect of SAHA treatment. Our results show for the first time that C/EBPalpha with its associated direct core clock gene target, PER2, are highly deregulated in DLBCL, suggesting an important tumor suppressive pathway in the pathogenesis of this lymphoma entity.
ISSN:1042-8194
1029-2403
DOI:10.3109/10428194.2012.658792