title: Histone deacetylase 3 inhibits expression of PUMA in gastric cancer cells.
abstract: During cancer development, tumor suppressor genes were silenced by promoter methylation or histone deacetylation. Histone deacetylases (HDACs) are important to maintain histone deacetylation. HDAC inhibitors (HDACis) were thus proposed as a new therapeutic approach to cancer. The current study aims to understand the effect and molecular mechanisms of HDACis on gastric cancer cells. Trichostatin A (TSA) significantly inhibited the growth of gastric cancer cells by inducing apoptosis. Gene profiling results showed PUMA (p53 upregulated modulator of apoptosis) as one of 122 genes upregulated in TSA-treated gastric cancer cells. PUMA was downregulated in gastric cancer cell lines and primary gastric carcinoma tissues. Patients with low PUMA expression had significant decreases in overall survival (HR, 2.04; p = 0.047). Ectopic PUMA expression inhibited the growth of gastric cancer cells while PUMA depletion promoted cellular growth. The knockdown of HDAC3 but not other HDACs upregulated PUMA expression. HDAC3 could bind to PUMA promoter, which was abrogated after TSA treatment. In contrast to TSA and SB, HDAC3 siRNA failed to upregulate p53 expression but promoted the interaction of p53 with PUMA promoter. In summary, proapoptotic PUMA was downregulated in gastric cancer and its mRNA expression level is a valuable prognosis factor for gastric cancer. HDAC3 is important to downregulate PUMA expression in gastric cancer and HDACis, like TSA, promoted PUMA expression through stabilizing p53 in addition to HDAC3 inhibition. In combination with chemotherapy, targeting HDAC3 might be a promising strategy to induce apoptosis of gastric cancer cells.
authors: Laboratory of Cancer Epigenetics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Lifeng
authors: L
authors: Feng
authors: Min
authors: M
authors: Pan
authors: Jie
authors: J
authors: Sun
authors: Haiqi
authors: H
authors: Lu
authors: Qi
authors: Q
authors: Shen
authors: Shengjie
authors: S
authors: Zhang
authors: Tingting
authors: T
authors: Jiang
authors: Liangyi
authors: L
authors: Liu
authors: Wei
authors: W
authors: Jin
authors: Yan
authors: Y
authors: Chen
authors: Xian
authors: X
authors: Wang
authors: Hongchuan
authors: H
authors: Jin
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D051017:Apoptosis Regulatory Proteins; D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000099186:Histone Deacetylase 3; C438378:BBC3 protein, human; C012589:trichostatin A