表观遗传学

Cancer and epigenetics 癌症和表观遗传学

Cancer’s epicentre 癌症的震中

New understanding of how cancers work is yielding new treatments
癌症作用机制的新认识衍生新疗法
Apr 7th 2012 | CHICAGO | from the print edition




THE biggest conceptual breakthrough in the war on cancer was the realisation by the 1980s that it is always a genetic disease. Sometimes the genetic flaw is inherited. Sometimes it is the result of exposure to an outside agent such as tobacco smoke or radioactivity. Sometimes it is plain bad luck; a miscopying of a piece of DNA during the normal process of cell division.

二十世纪八十年代，在对癌战争中实现了最大的概念突破，癌症总是一种遗传性的疾病。遗传缺陷有时是通过遗传获得的，有时是接触烟草烟雾和放射线等外部诱导物的结果。有时只不过运气不佳，有些DNA在正常的细胞分裂过程中进行了错误的复制。

Turning that breakthrough into medicine, though, is hard. No one has worked out how to repair DNA directly. It is, rather, a question of discovering the biochemical consequences of the genetic damage and trying to deal with those instead. But recently, another pattern has emerged. It is too early to call it a breakthrough as significant as the cancer-is-caused-by-broken-genes finding, but it might be.

不过，把这种突破转变成临床突破很难。没人解决过如何直接修复DNA的问题。更准确地说，就是揭秘遗传损伤的生化后果，并试图处理这些改变。但最近，又出现了另一种模式。把它称为重大突破还言之尚早，它的重大意义还赶不上癌症是由基因损伤造成的这一发现，但它有可能是重大突破。

The pattern in question is that many of the genes whose breakage leads to cancer are themselves involved in a specific sort of genetic regulation, known as epigenetics. This switches genes on and off by plastering either their DNA or the proteins which support that DNA in chromosomes with clusters of atoms called methyl and acetyl groups. The nature of these reactions means epigenetic processes are susceptible to chemical intervention in a way that genetic mutations are not. They are, in other words, open to drug treatment. And that is why epigenetics was the subject of a particularly interesting session, held on April 1st, at a meeting of the American Association for Cancer Research in Chicago.

这里提到的模式就是许多导致癌症的受损基因其本身涉及了特定的基因调控，称为表观遗传学。这一模式通过DNA或支撑染色体DNA的蛋白质甲基化和乙酰基化来开关基因。这些反应的本质意味着表观遗传过程易受化学干预的影响，而基因突变则不受这些影响。换句话说，它们能够接受药物治疗。这就是在美国芝加哥癌症研究协会的会议上，为什么表观遗传学会成为4月1日召开的一次特别有趣的例会的主题。

A problem of overregulation过度监管的问题

Dash Dhanak, who leads the epigenetics research group at GlaxoSmithKline, one of the world’s biggest drug companies, described to the meeting his efforts to develop a substance that will inhibit the activity of an enzyme called EZH2. This enzyme attaches methyl groups to histone proteins, which are part of the chromosomal packaging. A lot of lymphomas—cancers of the immune system—are caused by mutations that make EZH2 overactive. Such overactivity methylates histones more than they should be and thus silences the genes they surround, including so-called tumour-suppressor genes whose job is to stop the uncontrolled cell growth that causes cancer.

葛兰素史克公司是世界上最大的制药公司之一，戴斯•达纳克在这家公司带领一个表观遗传学研究小组，他在会议上介绍了他努力开发一种物质，能抑制一种EZH2酶的活性。这种酶催化参与了染色体包装的一部分组蛋白甲基化。淋巴瘤是免疫系统的癌症，大多是由于基因突变致使EZH2过度活跃造成的。这种过度活性使组蛋白甲基化的程度超出了应该的范围，因而沉默了相关的基因，包括所谓的抑癌基因，而抑癌基因的任务是阻止失控的细胞生长，避免导致癌症。

When Dr Dhanak and his colleagues treated lymphoma cells with a newly developed inhibitor, currently referred to by the unmemorable name GSK2816126, they found that the amount of histone overmethylation declined dramatically. And when they treated both cell cultures and laboratory animals with GSK2816126, they found it also reduces the proliferation of tumour cells while, crucially, having no apparent effect on nearby normal cells.

目前有种新开发的抑制剂叫GSK2816126，名称难记，达纳克博士和他的同事在用这种新开发的抑制剂处理淋巴瘤细胞时，他们发现组蛋白过度甲基化的数量急剧下降。他们用GSK2816126处理细胞培养物以及实验动物时发现，这种新开发的抑制剂也能减少肿瘤细胞的激增，同时至关重要的是它对附近正常的细胞没有明显的影响。

James Bradner of the Dana-Farber Cancer Institute, in Boston, described a second epigenetic approach to treating cancer. His group have shown that a substance known as JQ1, which inhibits an epigenetic regulator called BRD4, blocks the activity of a gene by the name of Myc. Myc encodes a protein called a transcription factor that is another part of the DNA-regulation system. This particular transcription factor is involved in the expression of about 15% of human genes. Not surprisingly, then, when it goes wrong it is one of the most common causes of cancer.

波士顿丹娜法伯癌症研究所的詹姆斯•布拉德纳描述了治疗癌症的第二种表观遗传学方法。他的小组已经证实，一种叫做JQ1的物质能抑制表观遗传调节剂BRD4，阻断Myc基因的活性。Myc基因替一种叫转录因子的蛋白质编码，转录因子是DNA调控体系的另外一部分。这个特定的转录因子参与了大约15％的人类基因表达。当它出错时就成了癌症最常见的原因之一，这点毫不奇怪。

Despite numerous attempts, researchers have been unable to find a way to block the activity of Myc directly. Dr Bradner, however, reasoned that blocking BRD4, which is one of Myc’s collaborators, might do the job indirectly. To test this thought he and his colleagues treated mice suffering from Myc-driven myeloma with JQ1. And it worked. JQ1, they found, shut down Myc-activated genes and slowed the proliferation of myeloma cells.

尽管多次尝试，研究人员却一直无法找到一种方式来直接阻断 Myc基因的活性。然而，布拉德纳博士推断，阻断Myc基因的协作者之一BRD4可能会间接阻断其活性。为了测试这个想法，他和他的同事用JQ1处理患有Myc基因引发的骨髓瘤的小鼠。它起作用了。他们发现，JQ1关闭了激活Myc的基因，减缓了骨髓瘤细胞的增殖。

Although neither GSK2816126 nor JQ1 is ready for human trials, two other sorts of epigenetic drugs are already on the market. DNA-demethylating agents, in the form of azacitidine, sold as Vidaza by Celgene, of Summit, New Jersey, and decitabine, sold as Dacogen by Eisai, a Japanese company, are used to treat myelodysplastic syndromes, the precursors of acute myelogenous leukaemia. And histone-deacetylase inhibitors, made by Celgene and by Merck, another New Jersey-based firm, are being used to treat a rare illness called cutaneous T-cell lymphoma.

虽然GSK2816126和JQ1都没做好进行人体试验的准备，但有另外两种表观遗传药物已经上市了。DNA去甲基剂以阿扎胞苷的形式由新泽西州沙米特市Celgene公司用Vidaza为商品名销售，丁西他滨由日本Eisai公司用Dacogen为商品名销售，这两款药都用于治疗骨髓增生异常综合征，这种病是急性髓细胞性白血病的前兆。新泽西Celgene公司和新泽西另一家默克公司制造的组蛋白去乙酰酶抑制剂正在用于治疗一种罕见的皮肤T细胞淋巴瘤。

More recently, researchers led by Stephen Baylin at Johns Hopkins School of Medicine, in Baltimore, have shown that a combination of a histone-deacetylase inhibitor and azacitidine slowed tumour growth in some people with advanced lung cancer. This result was notable for two reasons. It was the first time epigenetic drugs had been deployed successfully against a solid tumour, rather than a leukaemia or a lymphoma (solid tumours are harder to treat, because the drug has to penetrate them). And, second, some of the participants in Dr Baylin’s study who did not show much response to the trial itself then went on to show an unexpectedly good reaction to the routine chemotherapeutic drugs which were employed on them next. Although it is too early to say for sure, Dr Baylin speculates that his epigenetic drugs altered the tumour cells in some lasting way that made them more susceptible to standard chemotherapy.

最近，巴尔的摩约翰斯•霍普金斯医学院的斯蒂芬•拜林带领的研究人员证实，组蛋白去乙酰酶抑制剂和阿扎胞苷的结合减缓了一些晚期肺癌病人的肿瘤生长。有两个原因让这一结果值得注意。表观遗传药物首次成功打击了固体肿瘤，而不是白血病或淋巴瘤，固体肿瘤更难治疗，因为药物必须得渗透进这些肿瘤。第二，有些参与拜林博士研究的人对试验本身没有表现出很大的反应，但对接下来用在他们身上的常规化疗药物表现出的反应出乎意料地好。虽然确定还言之过早，但拜林博士推测，他的表观遗传药物以某种持久的方式改变了肿瘤细胞，使它们更容易受到标准化疗的影响。

That is quite possible. Unlike other forms of gene regulation (those involving transcription factors, for example), epigenetic changes are passed on during cell division to daughter and granddaughter cells until they are actively erased. Once erased, though, they do not return. It might therefore be that epigenetic therapies can effect changes which stop a cancer growing without having to kill all its cells.

这完全有可能。表观遗传改变与其他形式的基因调节不同，例如，涉及转录因子的基因调节，它们会在细胞分裂过程中传递给女儿和孙女的细胞，直到被主动清除。不过一旦被清除，它们也就不会回来了。因此，或许表观遗传疗法能产生改变，再让产生的改变阻止癌症生长，而不必杀死所有的癌细胞。

That, indeed, appears to be what is happening in the case of GSK2816126. If it is, it would truly be a conceptual breakthrough, and epigenetics might justly take its place alongside genetics in the analysis and treatment of cancer.

的确，似乎在GSK2816126的存在下发生了什么。如果是的话，就真有了概念上的突破，在癌症的分析与治疗上，表观遗传学也能有充分理由跟基因学并驾齐驱。