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.

Keywords::

• Transcription factor
• circadian rhythm
• mature B-cell lymphoma

Acknowledgements

This work was in part funded by the Deutsche Forschungsgemeinschaft (DFG, Bonn, Germany: TH 1438/1-1; N.H.T.), Deutsche Krebshilfe e.V. (N.H.T., G.B.T.), the National Institutes of Health (NIH, Bethesda, MD: grant 5R01CA026038-32; H.P.K.) and an A*STAR grant of Singapore (National University of Singapore, Singapore; H.P.K). H.P.K. is the holder of the Mark Goodson endowed Chair in Oncology Research at Cedars-Sinai Medical Center and is a member of the Jonsson Cancer Center and the Molecular Biology Institute, UCLA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Potential conflict of interest

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