Systemic cell-cycle suppression by Apicidin, a histone deacetylase inhibitor, in MDA-MB-435 cells.
Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents for the treatment of solid and hematological malignancies. However, the best characterized HDAC function concerns the control of gene expression via the regulation of transcription activation or repression. To understand the genome-wide effects of HDAC inhibition on gene regulation, we performed serial gene expression analyses from 0 to 48 h after treating MDA-MB-435, a melanoma-derived highly metastatic tumor cell line, with Apicidin, a HDAC inhibitor. Combined-transcriptomic analysis of large-scale molecular changes induced by Apicidin resulted in the identification of 631 outlier genes that were continuously up- or down-regulated during the 48 h study period. When the 631 outlier genes were mapped to known biological processes, cell-cycle suppression emerged as the function most elicited by Apicidin. In addition comprehensive negative cell-cycle regulation by Apicidin was dissected using gene expression data and validated by Western blot analysis. We suggest the 631 outlier genes as a characteristic molecular signature for Apicidin, and propose concurrent transcriptional suppression of major components of cell-cycle regulatory circuit as potent anti-tumor mechanism of Apicidin. Genetic elements identified during this study also provide the possibility of novel therapeutic interventions in tumor metastasis.
Noh
Ji Heon
JH
Department of Pathology, College of Medicine and Microdissection Genomics Research Center, The Catholic University of Korea, Seoul, Korea.
Song
Jae Hwi
JH
Eun
Jung Woo
JW
Kim
Jeong Kyu
JK
Jung
Kwang Hwa
KH
Bae
Hyun Jin
HJ
Xie
Hong Jian
HJ
Ryu
Jae Chun
JC
Ahn
Young Min
YM
Wee
Seong Jun
SJ
Park
Won Sang
WS
Lee
Jung Young
JY
Nam
Suk Woo
SW
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D051900:Smad3 Protein; C102351:apicidin; D006655:Histone Deacetylases