Rocchi Paola, Tonelli Roberto, Camerin Consuelo, Purgato Stefania, Fronza Raffaele, Bianucci Fabrizio, Guerra Francesco, Pession Andrea, Ferreri Anna Maria
Department of Experimental Pathology, University of Bologna, Bologna, Italy.
Oncol Rep. 2005 Jun;13(6):1139-44.
Histone acetyltransferase and histone deacetylase (HDAC) determine the acetylation status of histones, and thereby control the regulation of gene expression. HDAC inhibitors have been found to inhibit the growth of a variety of tumor cells in vitro and in vivo. We demonstrated previously that the short-chain fatty acid compound butyrate and its derivative tributyrin (both HDAC inhibitors) arrest cell growth and induce differentiation in human neuroblastoma (NB) cells. In the current study we investigated the effect of the HDAC inhibitor valproic acid (VPA) on proliferation and differentiation in human NB cells (SJ-N-KP, AF8). Treatment with VPA resulted in a strong inhibition of cell proliferation and induction of cell differentiation, as revealed by neurite outgrowth and increase of acetylcholinesterase specific activity. Moreover, we addressed the question of whether the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1) are involved in the mechanism of action of members of the short-chain fatty acids class (VPA, sodium butyrate and tributyrin) of HDAC inhibitors, in human NB cells. We demonstrated that p21(Cip1) is a common target of induction of transcription and protein expression for all the three compounds, while only VPA induced a concomitant increase of p27(Kip1) gene expression. These results suggest that p21(Cip1) could be involved in the inhibition of proliferation and induction of differentiation in human NB cells induced by treatment with VPA or tributyrin or sodium butyrate. Moreover, p21(Cip1) could be applied in the molecular monitoring of drug action in the possible therapeutic application of these short-chain fatty acid members of HDAC inhibitors for human NB treatment.
组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC）决定组蛋白的乙酰化状态，从而控制基因表达的调控。已发现HDAC抑制剂在体外和体内均可抑制多种肿瘤细胞的生长。我们之前证明，短链脂肪酸化合物丁酸盐及其衍生物三丁酸甘油酯（均为HDAC抑制剂）可使人类神经母细胞瘤（NB）细胞的生长停滞并诱导其分化。在本研究中，我们调查了HDAC抑制剂丙戊酸（VPA）对人类NB细胞（SJ-N-KP、AF8）增殖和分化的影响。VPA处理导致细胞增殖受到强烈抑制并诱导细胞分化，这可通过神经突生长和乙酰胆碱酯酶比活性的增加得以体现。此外，我们探讨了细胞周期蛋白依赖性激酶抑制剂p21（Cip1）和p27（Kip1）是否参与HDAC抑制剂短链脂肪酸类成员（VPA、丁酸钠和三丁酸甘油酯）在人类NB细胞中的作用机制。我们证明p21（Cip1）是这三种化合物诱导转录和蛋白表达的共同靶点，而只有VPA可诱导p27（Kip1）基因表达同时增加。这些结果表明，p21（Cip1）可能参与VPA、三丁酸甘油酯或丁酸钠处理诱导的人类NB细胞增殖抑制和分化诱导过程。此外，在HDAC抑制剂的这些短链脂肪酸成员用于人类NB治疗的可能治疗应用中，p21（Cip1）可用于药物作用的分子监测。
