Acetylation of FoxO1 activates Bim expression to induce apoptosis in response to histone deacetylase inhibitor depsipeptide treatment.
Histone deacetylase (HDAC) inhibitors have been shown to induce cell cycle arrest and apoptosis in cancer cells. However, the mechanisms of HDAC inhibitor induced apoptosis are incompletely understood. In this study, depsipeptide, a novel HDAC inhibitor, was shown to be able to induce significant apoptotic cell death in human lung cancer cells. Further study showed that Bim, a BH3-only proapoptotic protein, was significantly upregulated by depsipeptide in cancer cells, and Bim's function in depsipeptide-induced apoptosis was confirmed by knockdown of Bim with RNAi. In addition, we found that depsipeptide-induced expression of Bim was directly dependent on acetylation of forkhead box class O1 (FoxO1) that is catalyzed by cyclic adenosine monophosphate-responsive element-binding protein-binding protein, and indirectly induced by a decreased four-and-a-half LIM-domain protein 2. Moreover, our results demonstrated that FoxO1 acetylation is required for the depsipeptide-induced activation of Bim and apoptosis, using transfection with a plasmid containing FoxO1 mutated at lysine sites and a luciferase reporter assay. These data show for the first time that an HDAC inhibitor induces apoptosis through the FoxO1 acetylation-Bim pathway.
Yang
Yang
Y
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, #38 Xueyuan Road, Beijing 100191, China.
Zhao
Ying
Y
Liao
Wenjuan
W
Yang
Jing
J
Wu
Lipeng
L
Zheng
Zhixing
Z
Yu
Yu
Y
Zhou
Wen
W
Li
Lian
L
Feng
Jingnan
J
Wang
Haiying
H
Zhu
Wei-Guo
WG
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D047630:Depsipeptides; D004791:Enzyme Inhibitors; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins