Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells.
Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells.
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发表时间：
1999-06
期刊：
影响因子：
11.2
通讯作者：
Haojie Huang;Christopher P. Reed;J. Zhang;V. Shridhar;Liang Wang;David C. Smith
中科院分区：
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作者：
Haojie Huang;Christopher P. Reed;J. Zhang;V. Shridhar;Liang Wang;David C. Smith
丁酸盐及其结构类似物最近作为一种潜在的晚期前列腺癌分化治疗药物进入临床试验。为了更好地了解前列腺癌分化的分子机制(S)，我们利用基因差异显示技术对丁酸诱导的基因(S)进行了鉴定。我们发现，经丁酸钠(NaBu)处理后，雄激素非依赖性前列腺癌PC-3细胞发生终末分化和凋亡。鉴定并鉴定了一种新的在NaBu诱导的PC-3细胞中表达上调的新基因，命名为羧基肽酶A3(CPA3)。该基因表达2795个碱基的信使核糖核酸，编码421个氨基酸的开放阅读框。CPA3与来自不同哺乳动物的锌蛋白有37-63%的氨基酸同源性。它还与几个非哺乳动物物种的锌CP有27-43%的氨基酸相似性，包括大肠杆菌、酵母、秀丽线虫和果蝇。CPA3与其最接近的同源物的结构相似性表明，CPA3蛋白含有一个16个残基的信号肽序列、一个95个残基的NH2末端激活片段和一个310个残基的CP酶结构域。在几种前列腺癌细胞系中，NaBu对CPA3的持续诱导使我们研究了参与CPA3mRNA诱导的信号通路。组蛋白脱乙酰酶的特异性抑制剂曲古抑素A也能诱导CPA3基因的表达，提示CPA3基因的诱导是通过组蛋白的超乙酰化来实现的。我们证明，CPA3的诱导是丁酸盐或曲古菌素A处理的下游效应，但p21(WAF1/CIP1)的诱导在这些处理后立即发生。我们还发现p21(WAF1/CIP1)反义mRNA的表达抑制了NaBu诱导CPA3的表达，表明p21的反义激活是NaBu诱导CPA3所必需的。我们的结果表明，在NaBu介导的PC-3细胞分化过程中，组蛋白高乙酰化信号通路被激活，新基因CPA3参与了这一途径。
Butyrate and its structural analogues have recently entered clinical trials as a potential drug for differentiation therapy of advanced prostate cancer. To better understand the molecular mechanism(s) involved in prostate cancer differentiation, we used mRNA differential display to identify the gene(s) induced by butyrate. We found that the androgen-independent prostate cancer cell line PC-3 undergoes terminal differentiation and apoptosis after treatment with sodium butyrate (NaBu). A novel cDNA designated carboxypeptidase A3 (CPA3), which was up-regulated in NaBu-treated PC-3 cells, was identified and characterized. This gene expresses a 2795-bp mRNA encoding a protein with an open reading frame of 421 amino acids. CPA3 has 37-63% amino acid identity with zinc CPs from different mammalian species. It also shares 27-43% amino acid similarity with zinc CPs from several nonmammalian species, including Escherichia coli, yeast, Caenorhabditis elegans, and Drosophila. The structural similarity between CPA3 and its closest homologues indicates that the putative CPA3 protein contains a 16-residue signal peptide sequence, a 95-residue NH2-terminal activation segment, and a 310-residue CP enzyme domain. The consistent induction of CPA3 by NaBu in several prostate cancer cell lines led us to investigate the signaling pathway involved in the induction of CPA3 mRNA. Trichostatin A, a potent and specific inhibitor of histone deacetylase, also induced CPA3 mRNA expression, suggesting that CPA3 gene induction is mediated by histone hyperacetylation. We demonstrated that CPA3 induction was a downstream effect of the treatment with butyrate or trichostatin A, but that the induction of p21(WAF1/CIP1) occurred immediately after these treatments. We also demonstrated that the induction of CPA3 mRNA by NaBu was inhibited by p21(WAF1/CIP1) antisense mRNA expression, indicating that p21 transactivation is required for the induction of CPA3 by NaBu. Our data demonstrate that the histone hyperacetylation signaling pathway is activated during NaBu-mediated differentiation of PC-3 cells, and the new gene, CPA3, is involved in this pathway.