a MRC Toxicology Unit , University of Cambridge , Leicester , UK.
b Beatson Institute for Cancer Research , Glasgow , UK.
Cell Cycle. 2019 May;18(9):963-975. doi: 10.1080/15384101.2019.1601476. Epub 2019 Apr 19.
Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice.
癌症的常见特征包括细胞周期进程的失调和基因组不稳定性的获得。在肿瘤中，G1 细胞周期检查点的诱导通常会丢失。这增加了对功能正常的 G2/M 检查点的依赖，以防止带有受损 DNA 的有丝分裂通过，从而避免潜在的异常遗传改变的引入。用电离辐射（IR）治疗肿瘤利用了对 G2/M 检查点的这种依赖性。因此，鉴定调节此过程的因素可以为完善这种广泛使用的癌症治疗方法提供重要的生物标志物。亮氨酸拉链和 ICAT 结构域包含（LZIC）下调与 IR 诱导肿瘤的发展有关。然而，尽管 LZIC 高度保守，但它没有已知的分子功能。我们证明 LZIC 敲除（KO）细胞系在 IR 处理后显示出失调的 G2/M 细胞周期检查点。此外，我们表明 LZIC 缺陷细胞能够有效地激活 G1 和早期 G2/M 检查点，但在暴露于 IR 后无法维持晚期 G2/M 检查点。具体而言，该缺陷发生在 PIKK 信号下游。LZIC KO 细胞表现出严重的非整倍体，表明基因组不稳定。此外，对癌症患者数据库数据的分析揭示了 LZIC 表达与几种癌症预后不良之间存在很强的相关性。我们的研究结果表明，LZIC 参与细胞对 IR 的反应，其表达水平可作为临床癌症实践中患者分层的生物标志物。
