Histone deacetylase inhibition results in a common metabolic profile associated with HT29 differentiation.
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-(13)C(2)]-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.
Alcarraz-Vizán
Gema
G
Boren
Joan
J
Lee
Wai-Nang Paul
WN
Cascante
Marta
M
Exp Mol Pathol. 2007 Feb;82(1):77-84
16574101
Oncol Rep. 2006 Feb;15(2):489-94
16391874
Biochem J. 2003 Mar 15;370(Pt 3):737-49
12429021
Cancer Lett. 2009 May 8;277(1):8-21
18824292
Am J Physiol. 1998 May;274(5):E843-51
9612242
Cancer Res. 2004 Feb 1;64(3):985-93
14871829
J Nutr Biochem. 2008 Sep;19(9):587-93
18061431
Adv Enzyme Regul. 2004;44:109-21
15581486
Blood. 2007 Mar 15;109(6):2571-8
17119113
Int J Cancer. 2006 Dec 15;119(12):2733-41
17019714
Int J Cancer. 2004 Nov 1;112(2):171-8
15352027
J Cell Biochem. 2009 Jul 1;107(4):600-8
19459166
Cancer Res. 2001 Dec 1;61(23):8492-7
11731433
J Biol Chem. 1989 Aug 5;264(22):12994-3004
2753898
Gut. 2000 Apr;46(4):507-14
10716680
J Biol Chem. 2003 Aug 1;278(31):28395-402
12750369
Cancer Res. 1994 Jun 15;54(12):3288-93
8205551
Eur J Nutr. 2003 Jan;42(1):43-9
12594540
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
Rev Recent Clin Trials. 2006 May;1(2):169-82
18473969
Adv Exp Med Biol. 1996;399:95-114
8937551
Biochem J. 1990 Jan 1;265(1):23-38
2405837
Int J Biochem Cell Biol. 2009 Jan;41(1):21-5
18845268
Surgery. 1998 Aug;124(2):161-9; discussion 169-70
9706134
Expert Opin Investig Drugs. 2002 Dec;11(12):1695-713
12457432
Mol Genet Metab. 2008 Dec;95(4):195-200
18977676
Anticancer Res. 2003 Mar-Apr;23(2A):1149-54
12820363
Oncogene. 2007 Aug 13;26(37):5450-67
17694086
Clin Cancer Res. 2008 May 15;14(10):3132-40
18483381
Biochim Biophys Acta. 2006 Mar-Apr;1759(3-4):141-51
16757381
Epigenetics. 2008 Jan-Feb;3(1):28-37
18326939
Eur J Biochem. 1997 Jun 1;246(2):548-56
9208949
Gastroenterology. 1982 Aug;83(2):424-9
7084619
Biochem Biophys Res Commun. 1998 Jun 29;247(3):833-7
9647779
J Biol Chem. 2006 May 12;281(19):13548-13558
16533812