FK228 induces mitotic catastrophe in A549 cells by mistargeting chromosomal passenger complex localization through changing centromeric H3K9 hypoacetylation.
Previous studies have shown that histone deacetylase inhibitors (HDACis) can kill cancer cells. In addition, HDACis can induce mitotic catastrophe in cancer cells due to insufficient localization of chromosomal passenger complex (CPC) to the centromere. However, the mechanisms behind these phenomena remain unclear. In this study, we found that a HDACi, FK228, affected multiple epigenetic modification characteristics of the centromere, including enhanced acetylation of histone H3 lysine 9 (H3K9), decreased trimethylation of H3K9, and decreased phosphorylation of histone H3 serine 10 (H3S10) and centromere protein A (CENP-A). These epigenetic changes implied that H3K9 hyperacetylation inhibits the CPC recruitment, induces impaired centromere assembly and function, and eventually leads to aberrant mitosis. These data suggested that hypoacetylation of histone in the pericentromere is the most important landmark for recruiting CPC and leading to the mitotic catastrophe in HDACi-induced killing of cancer cells.
Zhang
Xuhui
X
Department of Pathology, Beijing Institute of Basic Medical Sciences, China.
Zhang
Zhiyi
Z
Chen
Guozhu
G
Zhao
Ming
M
Wang
Di
D
Zhang
Xuemin
X
Du
Zhiyan
Z
Xu
Yuanji
Y
Yu
Xiaodan
X
D000107:Acetylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001324:Autoantigens / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002503:Centromere / Q000187:drug effects / Q000378:metabolism; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D047630:Depsipeptides; D006657:Histones; D012694:Serine; C087123:romidepsin; D008239:Lysine