Dataset Information

Peroxisome proliferator-activated receptor ? and C/EBP? synergistically activate key metabolic adipocyte genes by assisted loading.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) and CCAAT/enhancer binding protein ? (C/EBP?) are key activators of adipogenesis. They mutually induce the expression of each other and have been reported to cooperate in activation of a few adipocyte genes. Recently, genome-wide profiling revealed a high degree of overlap between PPAR? and C/EBP? binding in adipocytes, suggesting that cooperativeness could be mediated through common binding sites. To directly investigate the interplay between PPAR? and C/EBP? at shared binding sites, we established a fibroblastic model system in which PPAR? and C/EBP? can be independently expressed. Using RNA sequencing, we demonstrate that coexpression of PPAR? and C/EBP? leads to synergistic activation of many key metabolic adipocyte genes. This is associated with extensive C/EBP?-mediated reprogramming of PPAR? binding and vice versa in the vicinity of these genes, as determined by chromatin immunoprecipitation combined with deep sequencing. Our results indicate that this is at least partly mediated by assisted loading involving chromatin remodeling directed by the leading factor. In conclusion, we report a novel mechanism by which the key adipogenic transcription factors, PPAR? and C/EBP?, cooperate in activation of the adipocyte gene program.

SUBMITTER: Madsen MS

PROVIDER: S-EPMC3958030 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading.

Madsen Maria Stahl MS Siersbæk Rasmus R Boergesen Michael M Nielsen Ronni R Mandrup Susanne S

Molecular and cellular biology 20131230 6

Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) are key activators of adipogenesis. They mutually induce the expression of each other and have been reported to cooperate in activation of a few adipocyte genes. Recently, genome-wide profiling revealed a high degree of overlap between PPARγ and C/EBPα binding in adipocytes, suggesting that cooperativeness could be mediated through common binding sites. To directly investigate the interplay between ...[more]

PMID: 24379442

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Project description:The effects of adipocyte‑rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte‑rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM‑associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator‑activated receptor γ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3‑shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM‑educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.

Dataset Information

Peroxisome proliferator-activated receptor ? and C/EBP? synergistically activate key metabolic adipocyte genes by assisted loading.

Publications

Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading.

Similar Datasets

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