Time-Dependent Interaction between Differentiated Embryo Chondrocyte-2 and CCAAT/Enhancer-Binding Protein α Underlies the Circadian Expression of CYP2D6 in Serum-Shocked HepG2 Cells

Authors:
  • MIMiki Inoue
    Miki Inoue
  • NKNaoki Kusunose
    Naoki Kusunose
  • KKKeisuke Kakimoto
    Keisuke Kakimoto
  • YHYuichi Hanada
    Yuichi Hanada
  • ATAyumi Toi
    Ayumi Toi
  • YYYuji Yoshiyama
    Yuji Yoshiyama
  • FSFuyuki Sato
    Fuyuki Sato
  • KFKatsumi Fujimoto
    Katsumi Fujimoto
  • SOShigehiro Ohdo
    Shigehiro Ohdo
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Abstract
Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a pleiotropic transcription repressor that controls the expression of genes involved in cellular differentiation, hypoxia responses, apoptosis, and circadian rhythm regulation. Although a previous study demonstrated that DEC2 participates in the circadian control of hepatic metabolism by regulating the expression of cytochrome P450, the molecular mechanism is not fully understood. We reported previously that brief exposure of HepG2 cells to 50% serum resulted in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes. In this study, we found that the expression of CYP2D6, a major drug-metabolizing enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2 cells. DEC2 interacted with CCAAT/enhancer-binding protein (C/EBPα), accompanied by formation of a complex with histone deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce the expression of CYP2D6. The oscillation in the protein levels of DEC2 in serum-shocked HepG2 cells was nearly antiphase to that in the mRNA levels of CYP2D6. Transfection of cells with small interfering RNA against DEC2 decreased the amplitude of CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells. DEC2 seems to constitute a molecular link through which output components from the circadian clock are associated with the time-dependent expression of hepatic drug-metabolizing enzyme.

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