Histone deacetylase inhibition results in a common metabolic profile associated with HT29 differentiation |
| |
Authors: | Gema Alcarraz-Vizán Joan Boren Wai-Nang Paul Lee Marta Cascante |
| |
Institution: | (1) Department of Biochemistry and Molecular Biology, Faculty of Biology (Edifici Nou), University of Barcelona, Av. Diagonal 645, 08028 Barcelona, Spain;(2) Biomedicine Institute from University of Barcelona (IBUB), Av. Diagonal 645, 08028 Barcelona, Spain;(3) Department of Pediatrics, LA Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 West Carson Street RB1, Torrance, CA 90502, USA;(4) Present address: Cambridge Research Institute, Cancer Research-UK, Robinson Way, CB2 0RE Cambridge, UK; |
| |
Abstract: | Cell differentiation is an orderly process that begins with modifications in gene expression. This process is regulated by
the acetylation state of histones. Removal of the acetyl groups of histones by specific enzymes (histone deacetylases, HDAC)
usually downregulates expression of genes that can cause cells to differentiate, and pharmacological inhibitors of these enzymes
have been shown to induce differentiation in several colon cancer cell lines. Butyrate at high (mM) concentration is both
a precursor for acetyl-CoA and a known HDAC inhibitor that induces cell differentiation in colon cells. The dual role of butyrate
raises the question whether its effects on HT29 cell differentiation are due to butyrate metabolism or to its HDAC inhibitor
activity. To distinguish between these two possibilities, we used a tracer-based metabolomics approach to compare the metabolic
changes induced by two different types of HDAC inhibitors (butyrate and the non-metabolic agent trichostatin A) and those
induced by other acetyl-CoA precursors that do not inhibit HDAC (caprylic and capric acids). 1,2-13C2]-d-glucose was used as a tracer and its redistribution among metabolic intermediates was measured to estimate the contribution
of glycolysis, the pentose phosphate pathway and the Krebs cycle to the metabolic profile of HT29 cells under the different
treatments. The results demonstrate that both HDAC inhibitors (trichostatin A and butyrate) induce a common metabolic profile
that is associated with histone deacetylase inhibition and differentiation of HT29 cells whereas the metabolic effects of
acetyl-CoA precursors are different from those of butyrate. The experimental findings support the concept of crosstalk between
metabolic and cell signalling events, and provide an experimental approach for the rational design of new combined therapies
that exploit the potential synergism between metabolic adaptation and cell differentiation processes through modification
of HDAC activity. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|