Title:Comprehensive Analysis for Histone Acetylation of Human Colon Cancer Cells Treated with a novel HDAC Inhibitor
Volume: 20
Issue: 11
Author(s): Yunlong Zhao, Xiuli Fang, Ye Wang, Junmei Zhang, Sheng Jiang, Zhe Liu, Zhenyi Ma, Liyan Xu, Enmin Li and Kai Zhang
Affiliation:
Keywords:
Post-translational modifications (PTMs), histone, lysine acetylation, lysine butyrylation, HDACi.
Abstract: 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, methyaltion 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.
