Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation

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.

癌症的常见标志性特征包括细胞周期进程失调与基因组不稳定性的获得。在肿瘤中，G1细胞周期检验点（G1 cell cycle checkpoint）的诱导功能通常丧失。这使得肿瘤更加依赖具有正常功能的G2/M细胞周期检验点，以阻止受损DNA进入有丝分裂进程，从而避免引入潜在的异常遗传变异。电离辐射（IR）治疗肿瘤的原理正是利用了肿瘤对G2/M检验点的这种依赖性，因此，鉴定调控该过程的因子可为优化这一广泛应用的癌症治疗手段提供重要的生物标志物。含有亮氨酸拉链和ICAT结构域的蛋白（Leucine zipper and ICAT domain containing, LZIC）的表达下调，与电离辐射诱导的肿瘤发生相关。然而，尽管LZIC在进化中高度保守，但其分子功能至今尚未明确。本研究证实，LZIC敲除（KO）细胞系在接受IR处理后，其G2/M细胞周期检验点出现调控失调。此外，研究发现LZIC缺陷细胞可正常激活G1检验点与早期G2/M检验点，但在IR暴露后无法维持晚期G2/M检验点的功能；具体而言，该缺陷发生在PIKK信号通路的下游。LZIC敲除细胞表现出严重的非整倍体性，提示其存在基因组不稳定性。此外，通过对癌症患者数据库数据的分析，我们发现LZIC的表达水平与多种癌症患者的不良预后存在显著相关性。本研究结果表明，LZIC在细胞对IR的应答过程中发挥功能性作用，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。