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Genome Med. 2016 Jul 11;8(1):74. doi: 10.1186/s13073-016-0328-6.

Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation.

Author information

1
HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
2
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
3
Departments of Microbiology and Urology, New York University, New York, NY, 10016, USA.
4
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
5
HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA. rmyers@hudsonalpha.org.

Abstract

BACKGROUND:

The liver X receptors (LXRs, NR1H2 and NR1H3) and peroxisome proliferator-activated receptor gamma (PPARG, NR1C3) nuclear receptor transcription factors (TFs) are master regulators of energy homeostasis. Intriguingly, recent studies suggest that these metabolic regulators also impact tumor cell proliferation. However, a comprehensive temporal molecular characterization of the LXR and PPARG gene regulatory responses in tumor cells is still lacking.

METHODS:

To better define the underlying molecular processes governing the genetic control of cellular growth in response to extracellular metabolic signals, we performed a comprehensive, genome-wide characterization of the temporal regulatory cascades mediated by LXR and PPARG signaling in HT29 colorectal cancer cells. For this analysis, we applied a multi-tiered approach that incorporated cellular phenotypic assays, gene expression profiles, chromatin state dynamics, and nuclear receptor binding patterns.

RESULTS:

Our results illustrate that the activation of both nuclear receptors inhibited cell proliferation and further decreased glutathione levels, consistent with increased cellular oxidative stress. Despite a common metabolic reprogramming, the gene regulatory network programs initiated by these nuclear receptors were widely distinct. PPARG generated a rapid and short-term response while maintaining a gene activator role. By contrast, LXR signaling was prolonged, with initial, predominantly activating functions that transitioned to repressive gene regulatory activities at late time points.

CONCLUSIONS:

Through the use of a multi-tiered strategy that integrated various genomic datasets, our data illustrate that distinct gene regulatory programs elicit common phenotypic effects, highlighting the complexity of the genome. These results further provide a detailed molecular map of metabolic reprogramming in cancer cells through LXR and PPARG activation. As ligand-inducible TFs, these nuclear receptors can potentially serve as attractive therapeutic targets for the treatment of various cancers.

KEYWORDS:

Cell proliferation; ChIP-seq; Chromatin state dynamics; Energy homeostasis; LXR; Metabolism; Nuclear receptors; PPARG; RNA-seq; Transcription

PMID:
27401066
PMCID:
PMC4940857
DOI:
10.1186/s13073-016-0328-6
[Indexed for MEDLINE]
Free PMC Article

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