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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

The histone deacetylase inhibitor Vorinostat (SAHA) induces only Glut 3 and Glut-4 in NSCLC cell lines. (a) A549 and SK-MES-1 cell lines were treated with or without the histone deacetylase inhibitor Vorinostat (SAHA), and mRNA expression of various Glut family members were examined by RT-PCR. (b) Densitometric analysis of Glut-3 expression. Beta-actin levels were used for normalization purposes. Data is expressed as mean ± SEM. Statistical analysis was performed using a Student's t test. (UT, untreated; SAHA, Vorinostat).
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f2-cancers-03-01550: The histone deacetylase inhibitor Vorinostat (SAHA) induces only Glut 3 and Glut-4 in NSCLC cell lines. (a) A549 and SK-MES-1 cell lines were treated with or without the histone deacetylase inhibitor Vorinostat (SAHA), and mRNA expression of various Glut family members were examined by RT-PCR. (b) Densitometric analysis of Glut-3 expression. Beta-actin levels were used for normalization purposes. Data is expressed as mean ± SEM. Statistical analysis was performed using a Student's t test. (UT, untreated; SAHA, Vorinostat).

Mentions: We examined the expression of various other Glut family members in the A549 and SK-MES-1cell lines for responses to HDACi. Glut1 was expressed in both cell lines but was not induced by SAHA (Figure 2a, and data not shown). Of the other Glut family members screened, Glut-3 was also found to be increased in these cell lines in response to HDAC inhibition (Figure 2b).


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)

The histone deacetylase inhibitor Vorinostat (SAHA) induces only Glut 3 and Glut-4 in NSCLC cell lines. (a) A549 and SK-MES-1 cell lines were treated with or without the histone deacetylase inhibitor Vorinostat (SAHA), and mRNA expression of various Glut family members were examined by RT-PCR. (b) Densitometric analysis of Glut-3 expression. Beta-actin levels were used for normalization purposes. Data is expressed as mean ± SEM. Statistical analysis was performed using a Student's t test. (UT, untreated; SAHA, Vorinostat).
© Copyright Policy
Related In: Results  -  Collection

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

f2-cancers-03-01550: The histone deacetylase inhibitor Vorinostat (SAHA) induces only Glut 3 and Glut-4 in NSCLC cell lines. (a) A549 and SK-MES-1 cell lines were treated with or without the histone deacetylase inhibitor Vorinostat (SAHA), and mRNA expression of various Glut family members were examined by RT-PCR. (b) Densitometric analysis of Glut-3 expression. Beta-actin levels were used for normalization purposes. Data is expressed as mean ± SEM. Statistical analysis was performed using a Student's t test. (UT, untreated; SAHA, Vorinostat).
Mentions: We examined the expression of various other Glut family members in the A549 and SK-MES-1cell lines for responses to HDACi. Glut1 was expressed in both cell lines but was not induced by SAHA (Figure 2a, and data not shown). Of the other Glut family members screened, Glut-3 was also found to be increased in these cell lines in response to HDAC inhibition (Figure 2b).

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