组蛋白去乙酰化酶(HDACs)的研究进展
3.4联合血管生成因子，影响肿瘤组织血管移行与形成
Ha等[27]发现血管内皮生长因子(VEGF)在内皮细胞中通过一种VEFG受体2-磷脂酶Cγ-蛋白激酶C(PKC)-蛋白激酶D(PKD)依赖的途径刺激Ⅱ类HDACs中的HDAC5的磷酸化与核内输出，在PKD依赖的磷酸化中一HDAC5特异性缺失的突变体抑制VEGF介导的NR4A1(一种血管生成中的寡核受体)的表达、内皮细胞的移行与体外血管的形成。运用siRNA技术沉默HDAC5，发现成纤维细胞生长因子2(FGF2)与包括Slit2在内的血管生长导向因子的表达受到明显抑制，说明HDAC5亦可通过抑制对血管内皮细胞的毛细管式“芽生”起重要作用的血管生成基因(如FGF2与Slit2)发挥抗血管形成作用[28]。
在众多内源性促血管生成物质中,VEGF与肿瘤血管生成关系十分密切。朱芳等[29]研究发现：VEGF低表达的细胞株不出现血管生成拟态现象，VEGF高表达的细胞株不一定出现血管生成拟态现象，而有血管生成拟态现象的细胞株VEGF表达高，说明VEGF与血管生成拟态形成有一定关系，只有VEGF表达高的细胞才有形成血管生成拟态的潜能。HDACs通过与VEGF相互作用而影响组织血管移行与形成。
Wang等[30]亦发现Ⅱ类HDACs中的HDAC7通过PKC/PKD依赖的途径完成由VEGF介导的磷酸化及核内输出，此种由VEGF介导HDAC7的分子反应的信号通路对于VEGF诱导的内皮细胞的分化与移行是必需的，其通过抑制依赖或不依赖肌细胞促进因子2(MEF2)基因的表达而调控内皮细胞的功能[31];除此之外,Ⅱ类中的HDAC4、HDAC5亦可由VEGF介导完成磷酸化，其核内输出过程可不完全依赖于VEGF完成，提示其可能作用于不同的靶点而在VEGF诱导的血管生成过程中发挥作用[28]。
此外，Hait等[32]发现HDACs是S1P(鞘氨醇膦酸酯)在细胞内的直接靶标，其最初是一种存在于细胞核中具有生物活性的脂质信使，由2型鞘氨醇激酶(sphK2)产生。SphK2选择性聚集在编码细胞周期蛋白依赖性激酶抑制剂p21或转录调节因子c-fos的基因启动子上。S1P通过特异性结合HDAC1和HDAC2，抑制其活性，进而保护组氨酸末端赖氨酸不被去乙酰化，从而提高组蛋白H3乙酰化的程度，促进转录。
4展望
HDACs作为催化组蛋白去乙酰化作用的关键酶类，以其参与肿瘤细胞生长增殖与表达调控等诸多过程，在肿瘤发生发展的表观遗传学研究中日益引起学术界的关注与重视。现今研究多集中在已有的具备HDACs抑制活性的抗肿瘤药物的化学修饰与结构改造，以增强其药效及减轻毒副作用等，而从HDACs结构特点与生物学功能本身出发设计作用于特定靶点与特定通路的抗肿瘤药物尚在少数。随着结构生物学与计算机辅助药物设计等学科的发展，以HDACs为靶点开发具有抗肿瘤活性的新型HDACs抑制剂必将具有广阔的前景。
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