Limits...
Glycolytic metabolism influences global chromatin structure.

Liu XS, Little JB, Yuan ZM - Oncotarget (2015)

Bottom Line: But the interrelationship between tumor metabolism and chromatin architecture remain unclear.Using complementary methods including Micrococcal nuclease (MNase) digestion assay, electron microscope and immunofluorescence staining, we demonstrate that glycolysis inhibition by pharmacological and genetic approaches was associated with induction of compacted chromatin structure.This condensed chromatin status appeared to result chiefly from histone hypoacetylation as restoration of histone acetylation with an HDAC inhibitor reversed the compacted chromatin state.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

ABSTRACT
Metabolic rewiring, specifically elevated glycolytic metabolism is a hallmark of cancer. Global chromatin structure regulates gene expression, DNA repair, and also affects cancer progression. But the interrelationship between tumor metabolism and chromatin architecture remain unclear. Here we show that increased glycolysis in cancer cells promotes an open chromatin configuration. Using complementary methods including Micrococcal nuclease (MNase) digestion assay, electron microscope and immunofluorescence staining, we demonstrate that glycolysis inhibition by pharmacological and genetic approaches was associated with induction of compacted chromatin structure. This condensed chromatin status appeared to result chiefly from histone hypoacetylation as restoration of histone acetylation with an HDAC inhibitor reversed the compacted chromatin state. Interestingly, glycolysis inhibition-induced chromatin condensation impeded DNA repair efficiency leading to increased sensitivity of cancer cells to DNA damage drugs, which may represent a novel molecular mechanism that can be exploited for cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Both HDAC and HAT are involved in glycolysis induced histone acetylationThe level of lactate (A), pyruvate (B), acetyl-CoA (C) or HDAC activity (D) in 2-DG treated (10 mM, 24 h) or control A549 cells was measured. Data shown are average values of three experiments with error bar indicate mean ± s.d.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4414184&req=5

Figure 5: Both HDAC and HAT are involved in glycolysis induced histone acetylationThe level of lactate (A), pyruvate (B), acetyl-CoA (C) or HDAC activity (D) in 2-DG treated (10 mM, 24 h) or control A549 cells was measured. Data shown are average values of three experiments with error bar indicate mean ± s.d.

Mentions: The steady state of histone acetylation is determined by a balanced action of histone acetyltransferase (HAT) and histone deacetylase (HDAC) [6]. The reduced histone acetylation by glycolysis inhibition could result from a decreased activity of HAT or increased activity of HDAC. It has been reported that metabolites or intermediates of the glycolytic pathway contribute to histone modifications, for instance, Acetyl-CoA, which provides the acetyl group required for the acetylation reaction, stimulates histone acetylation [13]. Pyruvate and lactate promote histone acetylation by inhibiting the activity of HDAC [14, 15]. We thus investigated the molecular mechanism underlying glycolysis-mediated modulation of histone acetylation by measuring the abundance of glycolytic metabolites. The result revealed that inhibition of glycolysis with 2-DG resulted in significant reduction of lactate, pyruvate and acetyl-CoA abundance (Figure 5A–5C). In addition, HDAC activity was found elevated in 2-DG-treated cells (Figure 5D). The results together suggest that glycolysis regulates histone acetylation via modulation of the activity of both HAT and HDAC. We also made an attempt to identify HDACs that were involved in glycolysis-mediated histone acetylation. To achieve this, we knocked down the expression of eleven HDACs individually or in combination. Results indicated that knockdown of multiple HDACs alleviated albeit partially the effect of 2-DG on global acetylation (Supplemental Figure S2), suggesting an involvement of multiple HDACs, which is consistent with previous reports showing that glycolytic metabolites were able to interfere with the activity of multiple HDACs [13, 14]. Knockdown of HDACs 3, 4 and 1/2/3/8 mix were unexpectedly associated with reduction of basal histone acetylation (Supplemental Figure S2), likely due to cellular toxicity.


Glycolytic metabolism influences global chromatin structure.

Liu XS, Little JB, Yuan ZM - Oncotarget (2015)

Both HDAC and HAT are involved in glycolysis induced histone acetylationThe level of lactate (A), pyruvate (B), acetyl-CoA (C) or HDAC activity (D) in 2-DG treated (10 mM, 24 h) or control A549 cells was measured. Data shown are average values of three experiments with error bar indicate mean ± s.d.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414184&req=5

Figure 5: Both HDAC and HAT are involved in glycolysis induced histone acetylationThe level of lactate (A), pyruvate (B), acetyl-CoA (C) or HDAC activity (D) in 2-DG treated (10 mM, 24 h) or control A549 cells was measured. Data shown are average values of three experiments with error bar indicate mean ± s.d.
Mentions: The steady state of histone acetylation is determined by a balanced action of histone acetyltransferase (HAT) and histone deacetylase (HDAC) [6]. The reduced histone acetylation by glycolysis inhibition could result from a decreased activity of HAT or increased activity of HDAC. It has been reported that metabolites or intermediates of the glycolytic pathway contribute to histone modifications, for instance, Acetyl-CoA, which provides the acetyl group required for the acetylation reaction, stimulates histone acetylation [13]. Pyruvate and lactate promote histone acetylation by inhibiting the activity of HDAC [14, 15]. We thus investigated the molecular mechanism underlying glycolysis-mediated modulation of histone acetylation by measuring the abundance of glycolytic metabolites. The result revealed that inhibition of glycolysis with 2-DG resulted in significant reduction of lactate, pyruvate and acetyl-CoA abundance (Figure 5A–5C). In addition, HDAC activity was found elevated in 2-DG-treated cells (Figure 5D). The results together suggest that glycolysis regulates histone acetylation via modulation of the activity of both HAT and HDAC. We also made an attempt to identify HDACs that were involved in glycolysis-mediated histone acetylation. To achieve this, we knocked down the expression of eleven HDACs individually or in combination. Results indicated that knockdown of multiple HDACs alleviated albeit partially the effect of 2-DG on global acetylation (Supplemental Figure S2), suggesting an involvement of multiple HDACs, which is consistent with previous reports showing that glycolytic metabolites were able to interfere with the activity of multiple HDACs [13, 14]. Knockdown of HDACs 3, 4 and 1/2/3/8 mix were unexpectedly associated with reduction of basal histone acetylation (Supplemental Figure S2), likely due to cellular toxicity.

Bottom Line: But the interrelationship between tumor metabolism and chromatin architecture remain unclear.Using complementary methods including Micrococcal nuclease (MNase) digestion assay, electron microscope and immunofluorescence staining, we demonstrate that glycolysis inhibition by pharmacological and genetic approaches was associated with induction of compacted chromatin structure.This condensed chromatin status appeared to result chiefly from histone hypoacetylation as restoration of histone acetylation with an HDAC inhibitor reversed the compacted chromatin state.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

ABSTRACT
Metabolic rewiring, specifically elevated glycolytic metabolism is a hallmark of cancer. Global chromatin structure regulates gene expression, DNA repair, and also affects cancer progression. But the interrelationship between tumor metabolism and chromatin architecture remain unclear. Here we show that increased glycolysis in cancer cells promotes an open chromatin configuration. Using complementary methods including Micrococcal nuclease (MNase) digestion assay, electron microscope and immunofluorescence staining, we demonstrate that glycolysis inhibition by pharmacological and genetic approaches was associated with induction of compacted chromatin structure. This condensed chromatin status appeared to result chiefly from histone hypoacetylation as restoration of histone acetylation with an HDAC inhibitor reversed the compacted chromatin state. Interestingly, glycolysis inhibition-induced chromatin condensation impeded DNA repair efficiency leading to increased sensitivity of cancer cells to DNA damage drugs, which may represent a novel molecular mechanism that can be exploited for cancer therapy.

No MeSH data available.


Related in: MedlinePlus