摘要
肿瘤发生发展是复杂且多步骤的过程,是遗传和表观遗传异常共同作用的结果。遗传变异能引起细胞增殖、分化和凋亡通路异常而导致肿瘤发生,越来越多的研究表明,表观遗传改变可引起癌基因的扩增或肿瘤抑制基因的沉默,在癌症的发生发展中同样发挥着重要作用。常见的表观遗传修饰包括基因启动子区域CpG岛甲基化、组蛋白修饰(包括组蛋白乙酰化和甲基化)、非编码RNA调控以及RNA的修饰。这些表观遗传变化不仅影响基因功能,还通过影响肿瘤微环境促使癌症特征的形成(包括持续增殖、抵抗治疗、血管生成、局部侵袭和远处转移)。本综述将重点阐述DNA甲基化和组蛋白乙酰化在介导肿瘤抗凋亡机制中的作用,并将讨论靶向表观遗传因子的抗肿瘤药物的发展现状及前景。
肿瘤的发生发展是一个复杂、多步骤的过程,是遗传和表观遗传异常共同作用下基因功能调节失控的结
表观遗传改变通过干扰独立于DNA序列的基因表达而影响遗传性状的表
研究癌症的表观遗传改变,并阐明其分子机制,将为癌症的早期检测和后期治疗提供新的思
DNA甲基化是指在DNA甲基转移酶(DNA methyltransferase, DNMT)的催化下,一个甲基基团共价转移到DNA胞嘧啶环的C-5位置的过程。DNA甲基化是细胞发育、细胞分化和组织稳态过程中的重要调控机制,与部分生理和病理过程有关,可引起一些表观遗传修
组蛋白修饰是指组蛋白在相关酶作用下发生甲基化、乙酰化、磷酸化、腺苷酸化、泛素化、ADP核糖基化等修饰的过程。组蛋白修饰发生在不同的组蛋白、组蛋白变体和组蛋白残基中,包括赖氨酸、精氨酸和丝氨
表观遗传因子在癌细胞增殖和存活中发挥着重要的调控作用。本文主要选取4种具有代表性的恶性肿瘤——恶性程度较高的肝细胞癌、肺癌以及男女发病率分别位居前列的前列腺癌、乳腺癌——来阐述DNA甲基化和组蛋白修饰两种表观遗传学调控方式与肿瘤发生发展的关系。
在肝细胞癌(hepatocellular carcinoma, HCC)样本中,已经鉴定出大约3 700个被低甲基化的启动
在HCC细胞增殖和存活过程中,组蛋白甲基化修饰起着重要作用。例如,果蝇zeste基因增强子人类同源物2(enhancer of zeste homolog 2, EZH2)是一种负责催化H3K27甲基化的酶,其在HCC组织中表达上调,与肿瘤扩散和疾病进展相
组蛋白乙酰化修饰对HCC也至关重要。在HCC中,HDACs常常高表达,且具有促癌作
在原发性乳腺肿瘤或乳腺癌(breast cancer, BC)细胞系中,有超过100个基因高甲基
在三阴性BC中,乳腺癌1号基因(breast cancer 1, BRCA1)是经典的肿瘤抑制基因之一,它的表观失活被认为是影响BC细胞存活的重要原
在肺癌中,有164个参与细胞分化和细胞周期调控的基因被DNA甲基化沉
在前列腺癌(prostate cancer, PCa)中,谷胱甘肽S-转移酶P1基因(glutathione S-transferase P1, GSTP1)是最早被发现的高甲基化基因之一,它参与解毒和清除潜在的遗传毒性化合物,防止DNA损伤和肿瘤转化的发生,且在PCa的所有阶段都呈高度甲基
在癌症的发生发展中,表观遗传改变是可逆的,因此表观遗传因子成为治疗癌症的重要靶
种类 | 作用 | 机制 | 特点 | 缺陷 | 文献 |
---|---|---|---|---|---|
DNMT 抑制剂 | 抑制DNMTs活性,影响细胞凋亡、细胞周期和免疫调节等 |
1)激活异常沉默的TSGs; 2)上调免疫共刺激分子的表达; 3)促进癌细胞新抗原的提呈 | 可以使DNA甲基化沉默的基因重新表达 |
1)基因表达可能大规模变化; 2)在实体瘤中活性较差; 3)伴有严重的毒副作用 |
[ |
HDAC 抑制剂 | 抑制HDACs活性,诱导癌细胞周期阻滞、分化、凋亡、减少血管生成和调节免疫应答等 |
1)上调CDKN1A的表达; 2)激活多种死亡受体和配体; 3)调控多种促凋亡基因的转录 |
1)耐受性较好; 2)毒副作用较轻 | 不能激活因启动子甲基化而导致的沉默基因的表达 |
[ |
基因启动子区CpG岛高甲基化是肿瘤中最常见的表观遗传改变之一,也是最吸引人的治疗靶点。DNMT抑制剂(DNA methyltransferase inhibitor, DNMTi)通过诱导低甲基化使双链DNA断裂,影响细胞凋亡、细胞周期和免疫调节等关键调控途
尽管DNMTis具有较好的临床疗效,但它们的药物作用位点是非特异性的,这意味着其不仅会诱导肿瘤中沉默不当的基因重新表达,还可能激活癌基因和促转移基因。此外,DNMTis对实体瘤的活性较差,且伴有严重的毒副作
HDACis通过抑制HDACs来增强组蛋白乙酰化修饰和基因表达,对癌细胞有广泛的影响,例如可诱导癌细胞周期阻滞、分化、凋亡,减少血管生成和调节免疫应
HDACis按结构可分为4大类:(1)短链脂肪酸类,如苯基丁酸、丁酸和丙戊酸;(2)羟肟酸类,如trichostatin A、vorinostat;(3)环四肽类,如trapoxin A、apicidin、FR901228;(4)苯酰胺类,如tacedinaline、domatinostat、mocetinostat、entinostat。其中前3大类属于HDAC非选择性抑制剂,主要治疗血液肿瘤,而最后一类苯酰胺类是选择性抑制剂,主要用于实体瘤治疗。目前有4款HDACis已获得FDA批准上市,分别是伏立诺他、罗米地辛、贝利司他、帕比司他(
药物名称 | 作用 | 机制 | 适应证 | 特点 | 文献 |
---|---|---|---|---|---|
伏立诺他 (vorinostat) | 诱导癌细胞周期阻滞、分化、凋亡 | 产生氧化应激反应、诱导DNA损伤和基因组不稳定性、激活TSGs表达以及通过乙酰化和基因组的不稳定性调节蛋白质的活性 | 复发/难治性皮肤T细胞淋巴瘤 | 对正常细胞毒性低,只有中等血液学毒性 |
[ |
罗米地辛 (romidepsin) | 抑制癌细胞增殖、分裂,诱导细胞周期阻滞和细胞凋亡 | 以一种不依赖于p53的方式上调p21/Cip1蛋白的表达,并下调Cdc2/Cdk-1和cyclin B1的表达 | 持续进展和复发T细胞淋巴瘤、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤 | 具有心脏毒性 |
[ |
帕比司他(panobinostat) | 诱导处于细胞周期G1期的细胞积累和凋亡 |
1)诱导组蛋白H3和H4乙酰化、上调p21表达、破坏Hsp90伴侣调控的功能; 2)提高Hsp90的乙酰化水平,从而降低Hsp90与EGFR、Akt和STAT3的结合力; 3)选择性消耗诸如EGFR、STAT3和Akt等蛋白,影响EGFR激酶突变细胞株的信号通路 | 多发性骨髓瘤 | 依赖表皮生长因子受体存活的细胞对帕比司他更为敏感 |
[ |
贝利司他(belinostat) | 抑制细胞增殖 |
1)抑制MAPK信号通路(ERK1/2和p38); 2)显著降低MAPK(MEK和B‐Raf)的磷酸化水平; 3)下调Sos蛋白的表达,但增强STAT3活性 | 外周T细胞淋巴瘤 | 不良反应可耐受,且几乎没有血液学毒性 |
[ |
阿扎胞苷(azacitidin) | 抑制细胞周期,诱导线粒体凋亡与自噬 |
1)通过启动子和基因去甲基化显著改变其甲基化和基因表达状态; 2)通过次要效应(包括改变上游基因、转录因子或元件的甲基化状态)改变基因表达 | 骨髓增生异常综合征、急性非淋巴细胞性白血病 |
1)不改变基因本身的甲基化状态; 2)可被并入DNA链和RNA链中 |
[ |
地西他滨(decitabine) | 诱导细胞周期阻滞和凋亡 | 骨髓增生异常综合征 |
1)不改变基因本身的甲基化状态; 2)只能被合并到DNA链中 |
[ |
目前有许多HDACis和DNMTis正在进行临床试验。通过检索clinicaltrials.gov共发现10项HDACis和3项DNMTis研究,采用单药治疗不同的肿瘤类型,并正处于临床试验的不同阶段(
药物名称 | 适应证 | 目前阶段 | 作用靶点 | NCT编号 |
---|---|---|---|---|
REC-2282 | 神经纤维瘤病2型 | Ⅱ/Ⅲ | pan-HDAC | 05130866 |
panobinostat | 急性髓系白血病、骨髓增生异常综合征、骨肉瘤、恶性横纹肌样肿瘤/非典型畸胎样/横纹肌样肿瘤、神经母细胞瘤 | Ⅱ/Ⅲ | pan-HDAC | 04326764、04897880 |
entinostat | 神经内分泌肿瘤 | Ⅱ | HDAC1/3 | 03211988 |
givinostat | 慢性骨髓增殖性肿瘤 | Ⅱ | HDAC1/2 | 01761968 |
abexinostat | 滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤 | Ⅰ/Ⅱ | pan-HDAC | 03934567、03936153、04024696 |
tinostamustine | 多种血液系统恶性肿瘤、实体瘤 | Ⅰ/Ⅱ | pan-HDAC | 02576496、03345485 |
fimepinostat | 弥漫性内源性脑桥胶质瘤、复发性髓母细胞瘤、复发性高级别胶质瘤 | Ⅰ | HDAC1/2、PI3K | 03893487 |
HG146 | 多发性骨髓瘤 | Ⅰ | HDAC1/2 | 03710915 |
NBM-BMX | 晚期实体瘤 | Ⅰ | HDAC8 | 03808870、03726294 |
resminostat | 皮肤T细胞淋巴瘤、蕈样肉芽肿、塞扎里综合征 | Ⅰ | HDAC1/2/4 | 04955340 |
guadecitabine | 骨髓增生异常综合征、急性髓系白血病 | Ⅱ | DNMT1、DNMT3A/3B | 03454984、03603964 |
Aza-TdC | 晚期实体瘤 | Ⅰ | DNMT1 | 03366116 |
NTX-301 | 急性髓系白血病、骨髓增生异常综合征、慢性粒单核细胞白血病 | Ⅰ | DNMT1 | 04167917 |
DNA甲基化和组蛋白乙酰化联合作用诱导肿瘤发生发展的机制,为表观遗传学联合疗法的组合方法提供了思
以表观遗传因子为靶点的治疗方法还可增强其他抗肿瘤治疗手段(包括放疗和化疗)的效果,在某些情况下,甚至能逆转患者的获得性耐
在过去十年中,表观遗传因素在癌症中的重要性已获得公认,并迅速发展为肿瘤基础与靶向治疗研究的新兴领
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