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Epigenetic regulation of glucose transporters in non-small cell lung cancer.

O'Byrne KJ, Baird AM, Kilmartin L, Leonard J, Sacevich C, Gray SG - Cancers (Basel) (2011)

Bottom Line: Due to their inherently hypoxic environment, cancer cells often resort to glycolysis, or the anaerobic breakdown of glucose to form ATP to provide for their energy needs, known as the Warburg effect.Similar results for GLUT-4 were observed in cells derived from liver, muscle, kidney and pre-adipocytes.Chromatin immunoprecipitation studies demonstrate that the promoter for GLUT-4 is dynamically remodeled in response to HDACi.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Medicine, Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James´s Hospital, Dublin 8, Ireland. sgray@stjames.ie.

ABSTRACT
Due to their inherently hypoxic environment, cancer cells often resort to glycolysis, or the anaerobic breakdown of glucose to form ATP to provide for their energy needs, known as the Warburg effect. At the same time, overexpression of the insulin receptor in non-small cell lung cancer (NSCLC) is associated with an increased risk of metastasis and decreased survival. The uptake of glucose into cells is carried out via glucose transporters or GLUTs. Of these, GLUT-4 is essential for insulin-stimulated glucose uptake. Following treatment with the epigenetic targeting agents histone deacetylase inhibitors (HDACi), GLUT-3 and GLUT-4 expression were found to be induced in NSCLC cell lines, with minimal responses in transformed normal human bronchial epithelial cells (HBECs). Similar results for GLUT-4 were observed in cells derived from liver, muscle, kidney and pre-adipocytes. Bioinformatic analysis of the promoter for GLUT-4 indicates that it may also be regulated by several chromatin binding factors or complexes including CTCF, SP1 and SMYD3. Chromatin immunoprecipitation studies demonstrate that the promoter for GLUT-4 is dynamically remodeled in response to HDACi. Overall, these results may have value within the clinical setting as (a) it may be possible to use this to enhance fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) imaging sensitivity; (b) it may be possible to target NSCLC through the use of HDACi and insulin mediated uptake of the metabolic targeting drugs such as 2-deoxyglucose (2-DG); or (c) enhance or sensitize NSCLC to chemotherapy.

No MeSH data available.


Related in: MedlinePlus

Detection of Glut-4 mRNA in cells following recovery from HDAC inhibition. Cells were treated for 24 hours with SAHA and either processed immediately or had fresh media without drug replaced and allowed to recover for a further 24 hours. (a) In A549 cells SAHA induced Glut-4 levels returned to basal levels following recovery. In contrast, (b) 24 hours post-recovery Glut-4 mRNA was readily detectable in SK-MES-1 cells (UT, untreated; SAHA, Vorinostat).
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f5-cancers-03-01550: Detection of Glut-4 mRNA in cells following recovery from HDAC inhibition. Cells were treated for 24 hours with SAHA and either processed immediately or had fresh media without drug replaced and allowed to recover for a further 24 hours. (a) In A549 cells SAHA induced Glut-4 levels returned to basal levels following recovery. In contrast, (b) 24 hours post-recovery Glut-4 mRNA was readily detectable in SK-MES-1 cells (UT, untreated; SAHA, Vorinostat).

Mentions: To determine if the induction of Glut-4 mRNA in response to histone deacetylase inhibition is sustained, cells were treated with SAHA for 24 hours and either processed directly or the media replaced and the cells allowed to recover for a further 24 hours. In A549 cells Glut-4 mRNA returned to basal levels within 24 hours (Figure 5a), while in SK-MES-1 a sustained elevation in Glut-4 mRNA is observed 24 hours following drug removal (Figure 5b).


Epigenetic regulation of glucose transporters in non-small cell lung cancer.

O'Byrne KJ, Baird AM, Kilmartin L, Leonard J, Sacevich C, Gray SG - Cancers (Basel) (2011)

Detection of Glut-4 mRNA in cells following recovery from HDAC inhibition. Cells were treated for 24 hours with SAHA and either processed immediately or had fresh media without drug replaced and allowed to recover for a further 24 hours. (a) In A549 cells SAHA induced Glut-4 levels returned to basal levels following recovery. In contrast, (b) 24 hours post-recovery Glut-4 mRNA was readily detectable in SK-MES-1 cells (UT, untreated; SAHA, Vorinostat).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757377&req=5

f5-cancers-03-01550: Detection of Glut-4 mRNA in cells following recovery from HDAC inhibition. Cells were treated for 24 hours with SAHA and either processed immediately or had fresh media without drug replaced and allowed to recover for a further 24 hours. (a) In A549 cells SAHA induced Glut-4 levels returned to basal levels following recovery. In contrast, (b) 24 hours post-recovery Glut-4 mRNA was readily detectable in SK-MES-1 cells (UT, untreated; SAHA, Vorinostat).
Mentions: To determine if the induction of Glut-4 mRNA in response to histone deacetylase inhibition is sustained, cells were treated with SAHA for 24 hours and either processed directly or the media replaced and the cells allowed to recover for a further 24 hours. In A549 cells Glut-4 mRNA returned to basal levels within 24 hours (Figure 5a), while in SK-MES-1 a sustained elevation in Glut-4 mRNA is observed 24 hours following drug removal (Figure 5b).

Bottom Line: Due to their inherently hypoxic environment, cancer cells often resort to glycolysis, or the anaerobic breakdown of glucose to form ATP to provide for their energy needs, known as the Warburg effect.Similar results for GLUT-4 were observed in cells derived from liver, muscle, kidney and pre-adipocytes.Chromatin immunoprecipitation studies demonstrate that the promoter for GLUT-4 is dynamically remodeled in response to HDACi.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Medicine, Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James´s Hospital, Dublin 8, Ireland. sgray@stjames.ie.

ABSTRACT
Due to their inherently hypoxic environment, cancer cells often resort to glycolysis, or the anaerobic breakdown of glucose to form ATP to provide for their energy needs, known as the Warburg effect. At the same time, overexpression of the insulin receptor in non-small cell lung cancer (NSCLC) is associated with an increased risk of metastasis and decreased survival. The uptake of glucose into cells is carried out via glucose transporters or GLUTs. Of these, GLUT-4 is essential for insulin-stimulated glucose uptake. Following treatment with the epigenetic targeting agents histone deacetylase inhibitors (HDACi), GLUT-3 and GLUT-4 expression were found to be induced in NSCLC cell lines, with minimal responses in transformed normal human bronchial epithelial cells (HBECs). Similar results for GLUT-4 were observed in cells derived from liver, muscle, kidney and pre-adipocytes. Bioinformatic analysis of the promoter for GLUT-4 indicates that it may also be regulated by several chromatin binding factors or complexes including CTCF, SP1 and SMYD3. Chromatin immunoprecipitation studies demonstrate that the promoter for GLUT-4 is dynamically remodeled in response to HDACi. Overall, these results may have value within the clinical setting as (a) it may be possible to use this to enhance fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) imaging sensitivity; (b) it may be possible to target NSCLC through the use of HDACi and insulin mediated uptake of the metabolic targeting drugs such as 2-deoxyglucose (2-DG); or (c) enhance or sensitize NSCLC to chemotherapy.

No MeSH data available.


Related in: MedlinePlus