title: HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses.
abstract: The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compounds that target the epigenome for the treatment of cancer. This notion is supported by biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through association with oncogenic fusion proteins such as PML-RARα and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biological and molecular responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific molecules and pathways in the tumor-selective cytotoxic activity of these compounds.
authors: Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne 3002, Victoria, Australia.
authors: J E
authors: JE
authors: Bolden
authors: W
authors: W
authors: Shi
authors: K
authors: K
authors: Jankowski
authors: C-Y
authors: CY
authors: Kan
authors: L
authors: L
authors: Cluse
authors: B P
authors: BP
authors: Martin
authors: K L
authors: KL
authors: MacKenzie
authors: G K
authors: GK
authors: Smyth
authors: R W
authors: RW
authors: Johnstone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D047630:Depsipeptides / Q000633:toxicity; D057890:Epigenomics; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity; D015778:Minor Histocompatibility Antigens; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060066:Protein Interaction Maps; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000077337:Vorinostat
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C096816:BCL2-related protein A1; C486655:BMF protein, human; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D000077337:Vorinostat; C087123:romidepsin; D006655:Histone Deacetylases