Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer.
To elucidate the molecular mechanisms for the enhancement of heat-induced apoptosis on exposure to acidic conditions, human maxillary carcinoma IMC-3 cells were heat-shocked at 44 degrees C for 30 min at either pH 7.4 or 6.7. Analyses with cDNA arrays, the reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting were performed. We found that histone deacetylase 3 (HDAC3) was specifically induced after hyperthermia at 44 degrees C for 30 min at pH 6.7. Although the cytotoxicity of heating at 44 degrees C for 30 min was enhanced by decreasing the pH from 7.4 to 6.7, it was enhanced even more by antisense RNA oligonucleotides for HDAC3. The induction of G2/M arrest after heating occurred earlier at pH 6.7 than at pH 7.4. The inhibition of HDAC3 by the antisense RNA oligonucleotides suppressed partially the induction of G2/M arrest, resulting in an enhancement of the apoptosis caused by the heating under acidic conditions. Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43 degrees C for 30 min in vivo. Analyses of p65 activity suggested that NF-kappaB is involved in this enhancement of hyperthermia. HDAC3 may be a novel target enhancing hyperthermia and combined treatment with hyperthermia and HDAC inhibitors is a possible modality for cancer therapy.
Narita
Norihiko
N
Department of Otorhinolaryngology, University of Fukui, Matsuoka, Fukui 910-1193, Japan. norihiko@fmsrsa.fukui-med.ac.jp
Fujieda
Shigeharu
S
Tokuriki
Masaharu
M
Takahashi
Noboru
N
Tsuzuki
Hideaki
H
Ohtsubo
Toshio
T
Matsumoto
Hideki
H
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D005434:Flow Cytometry; D016195:G2 Phase; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006979:Hyperthermia, Induced; D008441:Maxillary Neoplasms / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D000099186:Histone Deacetylase 3