In humans, exposure to light at night during shift work disrupts normal circadian rhythms, leading to an increased incidence of cancer;however, the molecular mechanisms underpinning circadian disruption in oncogenesis are not well understood. Nearly every cell in the human body has an endogenous molecular clock that controls integrated biochemical processes on a ~24-hour period. At the core of this molecular clock is the circadian basic helix-loop-helix Per:Arnt:Sim transcription factor complex CLOCK:BMAL1 that controls the rhythmic transcription of nearly 15% of the genome including essential genes in metabolism, hormone secretion and the cell cycle. In healthy somatic tissues the circadian clock and the cell cycle are linked such that the clock gates cell division to once a day thus preventing uncontrolled proliferation. The cell cycle/circadian link has been acknowledged for many years, however, the cellular perturbations that uncouple these two rhythmic systems in cancer remain to be elucidated. The objective of this proposal is to understand how a protein that is not expressed in healthy somatic tissues, yet is upregulated in cancer, represses the circadian clock and the effect of endogenous clock repression on cell proliferation. Our preliminary data show that this cancer-specific protein, PASD1, represses the activity of CLOCK:BMAL1. Based upon preliminary studies, our central hypothesis is that PASD1 silences clock function when expressed in cancer, removing clock-controlled homeostasis and cell cycle gating, leading cells down an oncogenic path. We will examine the role of PASD1 in clock regulation with the following specific aims: 1) Determine the mechanism by which PASD1 represses CLOCK:BMAL1 activity. Preliminary data demonstrate that a region of PASD1 that is conserved with a chromatin targeting domain in CLOCK is required for inhibition of CLOCK:BMAL1 activity. Our working hypothesis is that PASD1 uses molecular mimicry to interfere with the ability of CLOCK:BMAL1 to access target genes at the right time of day. To test this hypothesis we will perform ChIP-seq experiments to examine CLOCK:BMAL1 genomic targeting in the presence and absence of PASD1. 2) Determine how expression of PASD1 modulates circadian cycling and proliferation in human cancer cells. We hypothesize that knockdown of PASD1 in cancer cell lines will improve circadian cycling of CLOCK:BMAL1 target genes, providing more robust rhythms and decreased rates of proliferation. Investigating the mechanism by which a protein that is upregulated in cancer acts directly on the core circadian transcriptional feedback loop will establish a molecular link between circadian disruption and cancer with the long-term goal of identifying cancer therapeutics.
The proposed research aims to study the molecular link between disruption of daily rhythms and the development and progression of cancer. Understanding the consequence of perturbing this daily control on cellular health and tumor growth will allow for targeted cancer therapeutics for the prevention or treatment of this chronic disease.
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