title: 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 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.
authors.affiliation: Department of Hematology and Oncology, University Hospital of Münster, Münster, Germany. Nils.Thoennissen@ukmuenster.de
authors.forename: Nils H
authors.initials: NH
authors.lastname: Thoennissen
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Thoennissen
authors.forename: Sam
authors.initials: S
authors.lastname: Abbassi
authors.forename: Shayan
authors.initials: S
authors.lastname: Nabavi-Nouis
authors.forename: Tim
authors.initials: T
authors.lastname: Sauer
authors.forename: Ngan B
authors.initials: NB
authors.lastname: Doan
authors.forename: Sigal
authors.initials: S
authors.lastname: Gery
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D017209:Apoptosis; D001706:Biopsy; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002940:Circadian Rhythm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D008957:Models, Genetic; D056950:Period Circadian Proteins / Q000096:biosynthesis*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C421902:PER2 protein, human; D056950:Period Circadian Proteins