title: Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands.
abstract: Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands.
authors.affiliation: Princess Margaret Hospital, Ontario Cancer Institute, Ontario, Canada.
authors.forename: Tabitha E
authors.initials: TE
authors.lastname: Wood
authors.forename: Shadi
authors.initials: S
authors.lastname: Dalili
authors.forename: Craig D
authors.initials: CD
authors.lastname: Simpson
authors.forename: Mahadeo A
authors.initials: MA
authors.lastname: Sukhai
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Kika
authors.initials: K
authors.lastname: Anyiwe
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.forename: Fernando
authors.initials: F
authors.lastname: Suarez Saiz
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Yanina
authors.initials: Y
authors.lastname: Eberhard
authors.forename: Neil
authors.initials: N
authors.lastname: MacLean
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Robert A
authors.initials: RA
authors.lastname: Batey
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D053218:Receptors, Death Domain / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008024:Ligands; D053218:Receptors, Death Domain; D019014:fas Receptor; D006655:Histone Deacetylases