Dobosy Joseph R, Roberts J Lea W, Fu Vivian X, Jarrard David F
Division of Urology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Molecular and Environmental Toxicology Center, Madison, Wisconsin 53792, USA.
J Urol. 2007 Mar;177(3):822-31. doi: 10.1016/j.juro.2006.10.063.
Prostate cancer research has focused significant attention on the mutation, deletion or amplification of the DNA base sequence that encodes critical growth or suppressor genes. However, these changes have left significant gaps in our understanding of the development and progression of disease. It has become clear that epigenetic changes or modifications that influence phenotype without altering the genotype present a new and entirely different mechanism for gene regulation. Several interrelated epigenetic modifications that are altered in abnormal growth states are DNA methylation changes, histone modifications and genomic imprinting. We discuss the status of epigenetic alterations in prostate cancer and benign prostatic hyperplasia progression. In addition, the rationale and status of ongoing clinical trials altering epigenetic processes in urological diseases are reviewed.
An online search of current and past peer reviewed literature on DNA methylation, histone acetylation and methylation, imprinting and epigenetics in prostate cancer and benign prostatic hyperplasia was performed. Relevant articles and reviews were examined and a synopsis of reproducible data was generated with the goal of informing the practicing urologist of these advances and their implications.
Only 20 years ago the first study was published demonstrating global changes in DNA methylation patterns in tumors. Accumulating data have now identified specific genes that are commonly hypermethylated and inactivated during prostate cancer progression, including GSTpi, APC, MDR1, GPX3 and 14-3-3sigma. Altered histone modifications, including acetylation and methylation, were also recently described that may modify gene function, including androgen receptor function. These epigenetic changes are now being used to assist in prostate cancer diagnosis and cancer outcome prediction. Epigenetic changes appear to have a role in benign prostatic hyperplasia development as well as in the susceptibility of the prostate to developing cancer. Treatments involving 5-aza-deoxycytosine and other, more selective DNA methyltransferase inhibitors remove methyl residues from silenced genes, generating re-expression, and are currently being used in therapeutic trials. Histone deacetylase inhibitors have shown promise, not only by directly reactivating silenced genes, but also as regulators of apoptosis and sensitizers to radiation therapy.
Evolving data support a significant role for epigenetic processes in the development of prostate cancer and benign prostatic hyperplasia. Epigenetic changes can predict tumor behavior and often distinguish between genetically identical tumors. Targeted drugs that alter epigenetic modifications hold promise as a tool for curing and preventing these diseases.
前列腺癌研究主要聚焦于编码关键生长或抑制基因的DNA碱基序列的突变、缺失或扩增。然而，这些变化在我们对疾病发生和发展的理解上留下了重大空白。显然，影响表型而不改变基因型的表观遗传变化或修饰呈现出一种全新且截然不同的基因调控机制。在异常生长状态下发生改变的几种相互关联的表观遗传修饰包括DNA甲基化变化、组蛋白修饰和基因组印记。我们讨论了前列腺癌和良性前列腺增生进展过程中表观遗传改变的情况。此外，还综述了正在进行的改变泌尿系统疾病表观遗传过程的临床试验的基本原理和现状。
对当前和过去关于前列腺癌和良性前列腺增生中DNA甲基化、组蛋白乙酰化和甲基化、印记和表观遗传学的同行评审文献进行在线检索。查阅了相关文章和综述，并生成了可重复数据的概要，目的是让泌尿外科医生了解这些进展及其意义。
仅在20年前，第一项研究发表，证明肿瘤中DNA甲基化模式的全局变化。现在，越来越多的数据已经确定了在前列腺癌进展过程中通常会发生高甲基化并失活的特定基因，包括GSTpi、APC、MDR1、GPX3和14 - 3 - 3sigma。最近还描述了包括乙酰化和甲基化在内的组蛋白修饰的改变，这些改变可能会改变基因功能，包括雄激素受体功能。这些表观遗传变化现在正被用于辅助前列腺癌诊断和癌症预后预测。表观遗传变化似乎在良性前列腺增生的发生以及前列腺发生癌症的易感性中都起作用。涉及5 - 氮杂脱氧胞苷和其他更具选择性的DNA甲基转移酶抑制剂的治疗可从沉默基因中去除甲基残基，使基因重新表达，目前正用于治疗试验。组蛋白去乙酰化酶抑制剂已显示出前景，不仅通过直接重新激活沉默基因，还作为凋亡调节剂和放疗增敏剂。
不断发展的数据支持表观遗传过程在前列腺癌和良性前列腺增生发生中起重要作用。表观遗传变化可以预测肿瘤行为，并且常常能区分基因相同的肿瘤。改变表观遗传修饰的靶向药物有望成为治愈和预防这些疾病的工具。
