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Identification of a hormone response element that mediates suppression of APOF by LXR and PPAR? agonists.

ABSTRACT: Apolipoprotein F (ApoF) regulates cholesteryl ester transfer protein activity. We previously observed that hepatic APOF mRNA levels are decreased by high fat, cholesterol-enriched diets. Here we show in human liver C3A cells that APOF mRNA levels are reduced by agonists of LXR and PPAR? nuclear receptors. This negative regulation requires co-incubation with the RXR agonist, retinoic acid. Bioinformatic analysis of the ~2 kb sequence upstream of the APOF promoter identified one potential LXR and 4 potential PPAR? binding sites clustered between nucleotides -2007 and -1961. ChIP analysis confirmed agonist-dependent binding of LXR?, PPAR?, and RXR? to this hormone response element complex (HREc). A luciferase reporter containing the 2 kb 5' APOF sequence was negatively regulated by LXR and PPAR? ligands as seen in cells. This regulation was maintained in constructs lacking the ~1700 nucleotides between the HREc and the APOF proximal promoter. Mutations of the HREc that disrupted LXR? and PPAR? binding led to the loss of reporter construct inhibition by agonists of these nuclear receptors. siRNA knockdown studies showed that APOF gene regulation by LXR? or PPAR? agonists did not require an interaction between these two nuclear receptors. Thus, APOF is subject to negative regulation by agonist-activated LXR or PPAR? nuclear receptors binding to a regulatory element ~1900 bases 5' to the APOF promoter. High fat, cholesterol-enriched diets likely reduce APOF gene expression via these receptors interacting at this regulatory site.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6957717 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of a hormone response element that mediates suppression of APOF by LXR and PPARα agonists.

Liu Yan Y Izem Lahoucine L Morton Richard E RE

Biochimica et biophysica acta. Molecular and cell biology of lipids 20191206 3

Apolipoprotein F (ApoF) regulates cholesteryl ester transfer protein activity. We previously observed that hepatic APOF mRNA levels are decreased by high fat, cholesterol-enriched diets. Here we show in human liver C3A cells that APOF mRNA levels are reduced by agonists of LXR and PPARα nuclear receptors. This negative regulation requires co-incubation with the RXR agonist, retinoic acid. Bioinformatic analysis of the ~2 kb sequence upstream of the APOF promoter identified one potential LXR and ...[more]

PMID: 31812787

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Project description:Stromal Derived Factor-1? (SDF-1?) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) ?, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPAR?-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPAR? downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPAR? agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPAR?-mediated, since it was reversed in the presence of the PPAR? antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1?, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPAR? in inhibiting breast cancer progression and further highlight the utility of PPAR? ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.

Dataset Information

Identification of a hormone response element that mediates suppression of APOF by LXR and PPAR? agonists.

Publications

Identification of a hormone response element that mediates suppression of APOF by LXR and PPARα agonists.

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