title: Comprehensive analysis for histone acetylation of human colon cancer cells treated with a novel HDAC inhibitor.
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, 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.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xiuli
authors.initials: X
authors.lastname: Fang
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.forename: Junmei
authors.initials: J
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Ma
authors.forename: Liyan
authors.initials: L
authors.lastname: Xu
authors.forename: Enmin
authors.initials: E
authors.lastname: Li
authors.affiliation: School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Zhangkai730@aliyun.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D013844:Thiazoles; C527895:largazole; D006655:Histone Deacetylases