Myc-dependent mitochondrial generation of acetyl-CoA contributes to fatty acid biosynthesis and histone acetylation during cell cycle entry.
Cell reprogramming from a quiescent to proliferative state requires coordinate activation of multiple -omic networks. These networks activate histones, increase cellular bioenergetics and the synthesis of macromolecules required for cell proliferation. However, mechanisms that coordinate the regulation of these interconnected networks are not fully understood. The oncogene c-Myc (Myc) activates cellular metabolism and global chromatin remodeling. Here we tested for an interconnection between Myc regulation of metabolism and acetylation of histones. Using [(13)C(6)]glucose and a combination of GC/MS and LC/ESI tandem mass spectrometry, we determined the fractional incorporation of (13)C-labeled 2-carbon fragments into the fatty acid palmitate, and acetyl-lysines at the N-terminal tail of histone H4 in myc(-/-) and myc(+/+) Rat1A fibroblasts. Our data demonstrate that Myc increases mitochondrial synthesis of acetyl-CoA, as the de novo synthesis of (13)C-labeled palmitate was increased 2-fold in Myc-expressing cells. Additionally, Myc induced a forty percent increase in (13)C-labeled acetyl-CoA on H4-K16. This is linked to the capacity of Myc to increase mitochondrial production of acetyl-CoA, as we show that mitochondria provide 50% of the acetyl groups on H4-K16. These data point to a key role for Myc in directing the interconnection of -omic networks, and in particular, epigenetic modification of proteins in response to proliferative signals.
Morrish
Fionnuala
F
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Noonan
Jhoanna
J
Perez-Olsen
Carissa
C
Gafken
Philip R
PR
Fitzgibbon
Matthew
M
Kelleher
Joanne
J
VanGilst
Marc
M
Hockenbery
David
D
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D002247:Carbon Isotopes; D002453:Cell Cycle / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008055:Lipids / Q000032:analysis; D008239:Lysine / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D053719:Tandem Mass Spectrometry
D002247:Carbon Isotopes; D006657:Histones; D008055:Lipids; D010168:Palmitates; D016271:Proto-Oncogene Proteins c-myc; D000105:Acetyl Coenzyme A; D005947:Glucose; D008239:Lysine
J Biol Chem. 2009 Jan 16;284(3):1343-52
19015268
FEBS Lett. 1998 Oct 9;436(3):349-52
9801146
Oncogene. 2009 Jul 9;28(27):2485-91
19448666
Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
19033189
Science. 2009 May 22;324(5930):1076-80
19461003
EMBO J. 2006 Jun 21;25(12):2723-34
16724113
J Biol Chem. 2004 May 7;279(19):19574-9
14982940
Biochim Biophys Acta. 1962 May 21;59:487-9
13915992
Yeast. 1996 Dec;12(16):1607-33
9123965
Cell Metab. 2008 Jan;7(1):21-32
18177722
Lipids. 1976 Oct;11(10):774-7
994747
Mol Cell Biol. 2008 Jan;28(1):397-409
17967868
J Biol Chem. 2008 May 30;283(22):14927-37
18381279
Genome Biol. 2006;7(5):217
16689998
Mol Cell. 2006 Jul 21;23(2):207-17
16857587
Am J Physiol. 1997 Jun;272(6 Pt 1):E945-51
9227436
Am J Physiol. 1992 Oct;263(4 Pt 1):E667-75
1415685
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):5854-9
11972048
J Lipid Res. 2004 Jul;45(7):1324-32
15102881
Mol Cell Biol. 2005 Jul;25(14):6225-34
15988031
Oncogene. 2007 Aug 13;26(37):5310-8
17694074
Anal Biochem. 2003 May 1;316(1):23-33
12694723
Science. 2009 Aug 14;325(5942):834-40
19608861
Anal Chem. 1999 Jul 15;71(14):2871-82
10424174
Cell Cycle. 2008 Apr 15;7(8):1054-66
18414044
Nature. 2005 Mar 3;434(7029):113-8
15744310
Nature. 2000 Jan 6;403(6765):41-5
10638745