title: Myc-dependent mitochondrial generation of acetyl-CoA contributes to fatty acid biosynthesis and histone acetylation during cell cycle entry.
abstract: 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.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Fionnuala
authors.initials: F
authors.lastname: Morrish
authors.forename: Jhoanna
authors.initials: J
authors.lastname: Noonan
authors.forename: Carissa
authors.initials: C
authors.lastname: Perez-Olsen
authors.forename: Philip R
authors.initials: PR
authors.lastname: Gafken
authors.forename: Matthew
authors.initials: M
authors.lastname: Fitzgibbon
authors.forename: Joanne
authors.initials: J
authors.lastname: Kelleher
authors.forename: Marc
authors.initials: M
authors.lastname: VanGilst
authors.forename: David
authors.initials: D
authors.lastname: Hockenbery
mesh_terms: 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
chemical_list: D002247:Carbon Isotopes; D006657:Histones; D008055:Lipids; D010168:Palmitates; D016271:Proto-Oncogene Proteins c-myc; D000105:Acetyl Coenzyme A; D005947:Glucose; D008239:Lysine
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