基因组不稳定可驱动肿瘤发生发展。我们前期报道，转录因子KLF14是一个肿瘤抑制因子, 其低表达可驱动基因组不稳定进而诱发肿瘤；并同时报道其过表达可引发有丝分裂灾变（MC），但未阐明其机制。MC是一种由异常有丝分裂引起的细胞死亡。肿瘤细胞有DNA非整倍性和分裂频繁特征，使其更易诱发MC。MC诱发在肿瘤治疗中极具前景，但面临靶点少和机制不清双重瓶颈。我们提出KLF14是调控MC的新因子，进一步研究其下游基因及活性调控发现：KLF14很可能把控一批纺锤体、M期分裂、DNA损伤检查点基因转录进而调控MC，几种化疗药物在低浓度可刺激KLF14表达，KLF14沉默可抑制化疗药物诱发MC，KLF14有磷酸化和泛素化修饰并受药物调控，磷酸化可调控其MC诱发活性。本课题拟研究KLF14调控MC的分子路径及其修饰发生和活性调控机制，明确KLF14依赖的MC如何增敏放化疗，为肿瘤治疗提供新靶标和新思路。

Genomic instability is a driving force of carcinogenesis and progression. In our previous study, we have reported that the transcription factor KLF14 serves as a novel tumor suppressor, and its reduction promotes genomic instability, and as a consequence, tumorigenesis. In addition, in the same study, we also reported that forced expression of KLF14 leads to mitotic catastrophe (MC), but the mechanism for KLF14 overexpresion-induced MC is unclear. MC is a phenomenon of cell death caused by abnormal mitosis. Cancer cells can divide continually and a considerable fraction of cancer cells are aneuploid, which renders them intrinsically more susceptible to the induction of MC. MC appears to hold great promise for anticancer therapy. However, genes known to be involved in regulation of MC as well as to decipher the molecular mechanisms underlying MC are both limited. Here we suggest that KLF14 is a new factor in regulating MC. Further study on the downstream genes and the regulation mechanisms of KLF14, we observed that KLF14 may regulate MC via the transcriptional control of a series of the spindle, mitotic and DNA damage checkpoint genes, several chemotherapeutic agents at relatively low doses markedly improve the expression of KLF14, knockdown of KLF14 inhibits chemotherapeutic drugs-induced MC, KLF14 is highly posttranscriptional modified by phosphorylation and ubiquitination, levels of KLF posttranslational modifications can be regulated by chemotherapeutic agent, and phosphorylation of KLF14 regulates its MC-inducing activity. In this research proposal, we plan to study the KLF14 downstream genes involved in the regulation of MC, the mechanisms of KLF14 posttranslational modification, and the regulatory mechanisms of KLF14 activity, with aims to underscore the contribution of KLF14-dependent MC in sensitizing cancer cells to radiation and chemotherapy, and thus provide new targets and ideas for cancer treatment.