Transcription factor CCAAT/enhancer-binding protein alpha and critical circadian clock downstream target gene PER2 are highly deregulated in diffuse large B-cell lymphoma
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Transcription factor CCAAT/enhancer-binding protein alpha and critical circadian clock downstream target gene PER2 are highly deregulated in diffuse large B-cell lymphoma. / 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.
In: LEUKEMIA LYMPHOMA, Vol. 53, No. 8, 08.2012, p. 1577-85.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Transcription factor CCAAT/enhancer-binding protein alpha and critical circadian clock downstream target gene PER2 are highly deregulated in diffuse large B-cell lymphoma
AU - Thoennissen, Nils H
AU - Thoennissen, Gabriela B
AU - Abbassi, Sam
AU - Nabavi-Nouis, Shayan
AU - Sauer, Tim
AU - Doan, Ngan B
AU - Gery, Sigal
AU - Müller-Tidow, Carsten
AU - Said, Jonathan W
AU - Koeffler, H Phillip
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Biopsy
KW - CCAAT-Enhancer-Binding Protein-alpha
KW - Cell Cycle
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Cell Survival
KW - Circadian Rhythm
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Genes, Reporter
KW - Humans
KW - Lymphoma, Large B-Cell, Diffuse
KW - Models, Genetic
KW - Period Circadian Proteins
U2 - 10.3109/10428194.2012.658792
DO - 10.3109/10428194.2012.658792
M3 - SCORING: Journal article
C2 - 22260161
VL - 53
SP - 1577
EP - 1585
JO - LEUKEMIA LYMPHOMA
JF - LEUKEMIA LYMPHOMA
SN - 1042-8194
IS - 8
ER -