Boonsil Jang1, In-Hyoung Yang2, Nam-Pyo Cho2, Bohwan Jin3, WonWoo Lee3, Yun Chan Jung4, Seong Doo Hong5, Ji-Ae Shin6, Sung-Dae Cho7. 1. Department of Dental Hygiene, Sorabol College, Gyeongju 38063, Republic of Korea. 2. Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience and Biodegradable Material, Chonbuk National University, Jeonju 54896, Republic of Korea. 3. Laboratory Animal Center, CHA University, CHA Biocomplex, Sampyeong-dong, Seongnam 13488, Republic of Korea. 4. Chaon, 301-3, 240, Pangyoyeok-ro, Bundang-gu, Seongnam, Republic of Korea. 5. Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea. 6. Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea. Electronic address: sky21sm@snu.ac.kr. 7. Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea. Electronic address: efiwdsc@snu.ac.kr.
Abstract
OBJECTIVE: Sodium butyrate (NaBu) is a histone deacetylase inhibitor that possesses an apoptotic ability. However, the molecular mechanism by which NaBu induces apoptosis in human oral mucoepidermoid carcinoma (MEC), a type of salivary gland tumor, remains unclear. MATERIALS AND METHODS: The anticancer effects of NaBu and its related molecular mechanisms were determined by trypan blue exclusion assay, 4'-6-diamidino-2-phenylindole staining, live/dead assay, human apoptosis array, RT-PCR, western blotting, immunocytochemistry, preparation of nuclear fractions, and nude mice tumor xenograft. RESULTS: In this study, we found that NaBu inhibited growth and induced apoptosis in the human oral MEC cell lines MC3 and YD15 with acetylation of histone proteins H2A and H3. NaBu apparently down-regulated survivin protein, as evidenced by the results of the human apoptosis antibody array, and modulated it at the post-translational process. Interestingly, NaBu caused nuclear translocation of survivin protein in both cell lines. NaBu also resulted in decreased expression levels of Bcl-xL mRNA and protein, leading to induction of caspase-dependent apoptosis in human oral MEC cell lines. In addition, NaBu administration inhibited tumor growth in vivo at a dosage of 500 mg/kg/day, but it did not cause any hepatic or renal toxicity. CONCLUSION: This study provides new insights into the molecular mechanism of apoptotic actions by NaBu in human oral MEC and the basis of its clinical application for the treatment of human oral MEC.
OBJECTIVE:Sodium butyrate (NaBu) is a histone deacetylase inhibitor that possesses an apoptotic ability. However, the molecular mechanism by which NaBu induces apoptosis in humanoral mucoepidermoid carcinoma (MEC), a type of salivary gland tumor, remains unclear. MATERIALS AND METHODS: The anticancer effects of NaBu and its related molecular mechanisms were determined by trypan blue exclusion assay, 4'-6-diamidino-2-phenylindole staining, live/dead assay, human apoptosis array, RT-PCR, western blotting, immunocytochemistry, preparation of nuclear fractions, and nude micetumor xenograft. RESULTS: In this study, we found that NaBu inhibited growth and induced apoptosis in the human oral MEC cell lines MC3 and YD15 with acetylation of histone proteins H2A and H3. NaBu apparently down-regulated survivin protein, as evidenced by the results of the human apoptosis antibody array, and modulated it at the post-translational process. Interestingly, NaBu caused nuclear translocation of survivin protein in both cell lines. NaBu also resulted in decreased expression levels of Bcl-xL mRNA and protein, leading to induction of caspase-dependent apoptosis in human oral MEC cell lines. In addition, NaBu administration inhibited tumor growth in vivo at a dosage of 500 mg/kg/day, but it did not cause any hepatic or renal toxicity. CONCLUSION: This study provides new insights into the molecular mechanism of apoptotic actions by NaBu in human oral MEC and the basis of its clinical application for the treatment of human oral MEC.