Extensive evidence suggests that dysregulation of
histone lysine acetylation is intimately linked with the development of
cancer in epigenetic level.
Histone acetylation on
lysine is regulated mainly by the "pencil"--
Histone acetyltransferases (HATs) and the "eraser"--
Histone deacetylases HDACs. Dramatic elevation of global
histone deacetylation is considered as a
biomarker for
cancer. Therefore, current
antitumor drug design often targets HDACs, inhibiting overexpressed HDAC in
tumor cells with natural or synthesized small molecules like
largazole. Recently, a novel
largazole derivative (largazole-7) was designed and prepared by replacement of Val 1 with
tyrosine, and this modification increases selectivity toward human
cancer cells over normal cells more than 100-fold. However, it is unclear about the dynamic level of
histone acetylation under the treatment of this
drug. It is also unclear whether the other modifications are also affected by largazole-7 treatment. Therefore, a global mapping of modifications on the
histone proteins of
cancer cell line treated by this
drug may be of great benefit to elucidating its molecular mechanisms and exploring its potent as an
antitumor drug. To realize the goal, we combined stable
isotope labeling by
amino acids in cell culture (SILAC) and high resolution MS for comprehensive identification and quantitative analysis of
histone lysine acetylation and other modifications of Human
Colon Cancer Cells (HCT-116) with and without treatment of largazole-7. In this analysis, we identified 68
histone PTMs in 38 sites on core
histones, including
lysine acetylation, methylation and butyrylation, a novel
lysine modification. Further quantitative analysis not only discovered the global increased acetylated lysines, but also observed the changes of abundance of
lysine methylation and butyrylation under stimulation of the
drug. To our knowledge, it is the first report that regulation of largazole-7 against
lysine butyrylation. Our study expands the catalog of histone marks in
cancer, and provides an approach for understanding the known and new epigenetic marks under treatment of drugs.