title: Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Savic
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.|Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Ryne C
authors.initials: RC
authors.lastname: Ramaker
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Roberts
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Dean
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Burwell
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Meadows
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Cooper
authors.affiliation: Departments of Microbiology and Urology, New York University, New York, NY, 10016, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gertz
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA. rmyers@hudsonalpha.org.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
mesh_terms: D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004734:Energy Metabolism / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005978:Glutathione / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D000071518:Liver X Receptors / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; D047495:PPAR gamma; D005978:Glutathione
keywords: Cell proliferation; ChIP-seq; Chromatin state dynamics; Energy homeostasis; LXR; Metabolism; Nuclear receptors; PPARG; RNA-seq; Transcription