Histone acetylation-mediated regulation of genes in leukaemic cells.
Histone deacetylase (HDAC) and histone acetyltransferase (HAT) functions are associated with various cancers, and the inhibition of HDAC has been found to arrest disease progression. Here, we have investigated the gene expression profiles of leukaemic cells in response to the HDAC inhibitor trichostatin A (TSA) using oligonucleotide microarrays. Nucleosomal histone acetylation was monitored in parallel and the expression profiles of selected genes were confirmed by quantitative polymerase chain reaction (PCR). A large number of genes (9% of the genome) were found to be similarly regulated in CCRF-CEM and HL-60 cells in response to TSA, and genes showing primary and secondary responses could be distinguished by temporal analysis of gene expression. A small fraction of genes were highly sensitive to histone hyper-acetylation, including XRCC1, HOXB6, CDK10, MYC, MYB, NMI and CBFA2T3 and many were trans-acting factors relevant to cancer. The most rapidly repressed gene was MKRN3, an imprinted gene involved in the Prader-Willi syndrome.
Cancer Research UK Medical Oncology Laboratory, The Medical College of St. Bartholomew's Hospital, Charterhouse Square, London, EC1M 6QB, UK. annechambers@yahoo.co.uk
A E
AE
Chambers
S
S
Banerjee
T
T
Chaplin
J
J
Dunne
S
S
Debernardi
S P
SP
Joel
B D
BD
Young
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018922:HL-60 Cells; D051548:Histone Acetyltransferases; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; C012589:trichostatin A; D000123:Acetyltransferases; D051548:Histone Acetyltransferases