Chen T, Sun Y, Ji P, Kopetz S, Zhang W
1] Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Oncogene. 2015 Jul 30;34(31):4019-31. doi: 10.1038/onc.2014.332. Epub 2014 Oct 20.
Genome instability is a hallmark of cancer cells. Chromosome instability (CIN), which is often mutually exclusive from hypermutation genotypes, represents a distinct subtype of genome instability. Hypermutations in cancer cells are due to defects in DNA repair genes, but the cause of CIN is still elusive. However, because of the extensive chromosomal abnormalities associated with CIN, its cause is likely a defect in a network of genes that regulate mitotic checkpoints and chromosomal organization and segregation. Emerging evidence has shown that the chromosomal decatenation checkpoint, which is critical for chromatin untangling and packing during genetic material duplication, is defective in cancer cells with CIN. The decatenation checkpoint is known to be regulated by a family of enzymes called topoisomerases. Among them, the gene encoding topoisomerase IIα (TOP2A) is commonly altered at both gene copy number and gene expression level in cancer cells. Thus, abnormal alterations of TOP2A, its interacting proteins, and its modifications may have a critical role in CIN in human cancers. Clinically, a large arsenal of topoisomerase inhibitors has been used to suppress DNA replication in cancer. However, they often lead to the secondary development of leukemia because of their effect on the chromosomal decatenation checkpoint. Therefore, topoisomerase drugs must be used judiciously and administered on an individual basis. In this review, we highlight the biological function of TOP2A in chromosome segregation and the mechanisms that regulate this enzyme's expression and activity. We also review the roles of TOP2A and related proteins in human cancers, and raise a perspective for how to target TOP2A in personalized cancer therapy.
基因组不稳定是癌细胞的一个标志。染色体不稳定（CIN）通常与高突变基因型相互排斥，是基因组不稳定的一种独特亚型。癌细胞中的高突变是由于DNA修复基因的缺陷，但CIN的原因仍然难以捉摸。然而，由于与CIN相关的广泛染色体异常，其原因可能是调节有丝分裂检查点以及染色体组织和分离的基因网络存在缺陷。新出现的证据表明，在发生CIN的癌细胞中，对遗传物质复制过程中的染色质解缠和包装至关重要的染色体解连环检查点存在缺陷。已知解连环检查点受一类称为拓扑异构酶的酶家族调节。其中，编码拓扑异构酶IIα（TOP2A）的基因在癌细胞中通常在基因拷贝数和基因表达水平上都会发生改变。因此，TOP2A及其相互作用蛋白的异常改变以及其修饰可能在人类癌症的CIN中起关键作用。临床上，大量的拓扑异构酶抑制剂已被用于抑制癌症中的DNA复制。然而，由于它们对染色体解连环检查点的影响，它们常常导致白血病的二次发生。因此，拓扑异构酶药物必须谨慎使用并根据个体情况给药。在这篇综述中，我们强调了TOP2A在染色体分离中的生物学功能以及调节该酶表达和活性的机制。我们还综述了TOP2A及相关蛋白在人类癌症中的作用，并提出了在个性化癌症治疗中靶向TOP2A的前景。
