title: Chromatin structure predicts epigenetic therapy responsiveness in sarcoma.
abstract: To formally explore the potential therapeutic effect of histone deacetylase inhibitors (HDACI) and DNA-methyltransferase inhibitors (DNA-MI) on sarcomas, we treated a large sarcoma cell line panel with five different HDACIs in the absence and presence of the DNA-MI decitabine. We observed that the IC(50) value of each HDACI was consistent for all cell lines whereas decitabine as a single agent showed no growth inhibition at standard doses. Combination HDACI/DNA-MI therapy showed a preferential synergism for specific sarcoma cell lines. Subsequently, we identified and validated (in vitro and in vivo) a two-gene set signature (high CUGBP2; low RHOJ) that associated with the synergistic phenotype. We further uncover that the epigenetic synergism leading to specific upregulation of CDKI p21 in specific cell lines is a function of the differences in the degree of baseline chromatin modification. Finally, we show that these chromatin and gene expression patterns are similarly present in the majority of high-grade primary sarcomas. Our results provide the first demonstration of a gene set that can predict responsiveness to HDACI/DNA-MI and links this responsiveness mechanistically to the baseline chromatin structure.
authors.affiliation: Department of Pathology, Columbia University, New York, NY, USA.
authors.forename: Joslyn
authors.initials: J
authors.lastname: Mills
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.forename: Sara
authors.initials: S
authors.lastname: Siddiqi
authors.forename: Igor
authors.initials: I
authors.lastname: Matushansky
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics*; D016000:Cluster Analysis; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057890:Epigenomics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011897:Random Allocation; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors