Melnick Ari M, Adelson Kerin, Licht Jonathan D
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
J Clin Oncol. 2005 Jun 10;23(17):3957-70. doi: 10.1200/JCO.2005.14.498. Epub 2005 May 2.
Aberrant gene silencing is a frequent event in cancer and plays a critical role in the molecular pathogenesis of malignant transformation. The two major mechanisms of silencing in cancer include transcriptional repression by mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by hypermethylation of tumor suppressor or DNA repair-related genes. Both of these mechanisms require the activities of multiprotein chromatin remodeling and modifying machines, several of which may be mutated in cancer. The end result is genetic reprogramming of cells to express combinations of genes that confer the neoplastic phenotype. Recent discoveries in transcriptional biochemistry and gene regulation indicate that therapeutic agents can be engineered to specifically target these mechanisms. We provide a framework for the clinical or translational scientist to consider how such drugs might be developed and what their impact might be on restoring cells to normal genetic programming.
异常基因沉默在癌症中是常见事件，在恶性转化的分子发病机制中起关键作用。癌症中沉默的两个主要机制包括由突变或异常表达的转录因子引起的转录抑制，以及由肿瘤抑制基因或DNA修复相关基因的高甲基化导致的异常表观遗传沉默。这两种机制都需要多蛋白染色质重塑和修饰机器的活动，其中一些在癌症中可能发生突变。最终结果是细胞的基因重编程，以表达赋予肿瘤表型的基因组合。转录生物化学和基因调控方面的最新发现表明，可以设计治疗药物来特异性靶向这些机制。我们为临床或转化科学家提供一个框架，以考虑如何开发此类药物以及它们对使细胞恢复正常基因编程可能产生的影响。
