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Bmf contributes to histone deacetylase inhibitor-mediated enhancing effects on apoptosis after ionizing radiation
Yubin Zhang1, Masaaki Adachi, Rina Kawamura
1First Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1 W-16 Chuo-ku, Sapporo 060-8543, Japan.
Abstract:
Histone deacetylase (HDAC) inhibitors augment ionizing radiation (IR)-induced apoptosis in several cancer cells by undefined mechanism(s). We recently found that the HDAC inhibitors induce a BH3-only protein Bmf in human squamous carcinoma SAS cells. We extended this study and found that 2.5 nM FK228 pretreatment could not induce apoptosis but augmented IR-induced death. The FK228 pretreatment increased Bmf expression level, and siRNA-mediated knockdown of Bmf transcripts strongly inhibited its augmentation of IR-induced cell death, disruption of mitochondrial membrane potential and DNA fragmentation. Another HDAC inhibitor CBHA pretreatment similarly augmented IR-induced apoptosis, and this effect was also inhibited by Bmf knockdown. Bmf overexpression augmented IR-induced death, and the augmented effects of FK228 were similarly observed in another squamous carcinoma HSC2 cells. Overexpression of histone acetyltransferase p300 mimicked the effects of the HDAC inhibitors, i.e., it enhanced IR-induced death, which was mostly abolished by Bmf knockdown. Taken together, histone hyperacetylation may enhance IR-induced death via activation of Bmf transcription, thereby implying Bmf as a key molecule for HDAC inhibitors (FK228 and CBHA)-mediated enhancing effect on IR-induced cell death.
Insights
Histone deacetylase (HDAC) inhibitors enhance cancer cell death when combined with ionizing radiation (IR). This effect is mediated by the BH3-only protein Bmf, highlighting its role in augmenting IR-induced apoptosis.
Area of Science:
- Molecular Oncology
- Cancer Cell Death Mechanisms
- Epigenetics
Background:
- Histone deacetylase (HDAC) inhibitors are known to enhance cancer cell apoptosis induced by ionizing radiation (IR).
- The precise molecular mechanisms underlying this augmentation remain incompletely understood.
- Previous findings indicated that HDAC inhibitors induce the BH3-only protein Bmf in specific cancer cell lines.
Purpose of the Study:
- To investigate the role of the BH3-only protein Bmf in mediating the sensitizing effects of HDAC inhibitors on IR-induced cancer cell death.
- To explore the relationship between histone hyperacetylation and Bmf activation in response to HDAC inhibition and IR.
Main Methods:
- Treatment of human squamous carcinoma cells (SAS and HSC2) with HDAC inhibitors (FK228, CBHA) and/or IR.
- Assessment of apoptosis, cell death, mitochondrial membrane potential, and DNA fragmentation.
- Utilizing siRNA-mediated knockdown of Bmf transcripts and Bmf overexpression.
- Overexpression of histone acetyltransferase p300.
Main Results:
- FK228 pretreatment alone did not induce apoptosis but augmented IR-induced cell death.
- FK228 treatment increased Bmf expression; Bmf knockdown significantly inhibited the augmentation of IR-induced death, mitochondrial dysfunction, and DNA fragmentation.
- CBHA also augmented IR-induced apoptosis, an effect diminished by Bmf knockdown.
- Bmf overexpression enhanced IR-induced death, and FK228's effects were observed in another cell line (HSC2).
- p300 overexpression mimicked HDAC inhibitor effects, which were abolished by Bmf knockdown.
Conclusions:
- Histone hyperacetylation induced by HDAC inhibitors enhances IR-induced cancer cell death.
- This enhancement is significantly mediated through the activation of Bmf transcription.
- Bmf is identified as a key molecular player in the sensitizing effects of HDAC inhibitors like FK228 and CBHA on IR-induced cell death.
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