c-MYC targets the central oscillator gene Per1 and is regulated by the circadian clock at the post-transcriptional level

• Published in: Biochimica et biophysica acta Vol. 1859; no. 4; pp. 541 - 552
• Main Authors: Repouskou, Anastasia, Prombona, Anastasia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-04-2016
• Subjects: ARNTL Transcription Factors - genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; c-MYC; Carcinogenesis - genetics; Cell Line, Tumor; Cell Proliferation - genetics; Circadian; Circadian Rhythm - genetics; CLOCK Proteins - genetics; E-Box Elements - genetics; Gene Expression Regulation, Neoplastic; Humans; Neuroblastoma; Per-1; Period Circadian Proteins - genetics; Promoter Regions, Genetic; Protein Interaction Maps; Protein–protein interaction; Proto-Oncogene Proteins c-myc - genetics; Transcriptional regulation; Circadian; Transcriptional regulation; c-MYC; Protein–protein interaction; Per-1
• ISSN: 1874-9399; 0006-3002; 1876-4320
• DOI: 10.1016/j.bbagrm.2016.02.001

Cell proliferation in mammals follows a circadian rhythm while disruption of clock gene expression has been linked to tumorigenesis. Expression of the c-Myc oncogene is frequently deregulated in tumors, facilitating aberrant cell proliferation. c-MYC protein levels display circadian rhythmicity, which is compatible with an in vitro repressive role of the clock-activating complex BMAL1/CLOCK on its promoter. In this report, we provide evidence for the in vivo binding of the core circadian factor BMAL1 on the human c-Myc promoter. In addition, analysis of protein synthesis and degradation rates, as well as post-translational acetylation, demonstrate that the clock tightly controls cellular MYC levels. The oncoprotein itself is a transcription factor that by responding to mitogenic signals regulates the expression of several hundred genes. c-MYC-driven transcription is generally exerted upon dimerization with MAX and binding to E-box elements, a sequence that is also recognized by the circadian heterodimer. Our reporter assays reveal that the MYC/MAX dimer cannot affect transcription of the circadian gene Per1. However, when overexpressed, c-MYC is able to repress Per1 transactivation by BMAL1/CLOCK via targeting selective E-box sequences. Importantly, upon serum stimulation, MYC was detected in BMAL1 protein complexes. Together, these data demonstrate a novel interaction between MYC and circadian transactivators resulting in reduced clock-driven transcription. Perturbation of Per1 expression by MYC constitutes a plausible alternative explanation for the deregulated expression of clock genes observed in many types of cancer.
•Circadian clock regulates synthesis and degradation rate of c-MYC protein.•c-MYC is present in BMAL1 complexes in tumor cells, in vitro and in vivo.•Overexpressed c-MYC protein targets the proximal E-box of Per1 promoter.•c-MYC opposes transcriptional activity of BMAL1/CLOCK at the Per1 promoter.