Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia  

作　　者：Ting Guo Chen Miao Zhonghua Liu Jingwei Duan Yanbin Ma Xiao Zhang Weiwei Yang Maoguang Xue Qiannan Deng Pengfei Guo Yongmei Xi Xiaohang Yang Xun Huang Wanzhong Ge 

机构地区：[1]Division of Human Reproduction and Developmental Genetics,Women’s Hospital,Zhejiang University School of Medicine,Hangzhou 310058,China [2]Institute of Genetics,Zhejiang University School of Medicine,Hangzhou 310058,China [3]Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases,Women’s Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China [4]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China [5]Cancer Center,Zhejiang University,Hangzhou 310058,China

出　　处：《Journal of Molecular Cell Biology》2023年第12期50-64,共15页分子细胞生物学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(31970668).

摘　　要：Mutations or dysregulated expression of NF-kappaB-activating protein(NKAP)family genes have been found in human cancers.How NKAP family gene mutations promote tumor initiation and progression remains to be determined.Here,we characterized dNKAP,the Drosophila homolog of NKAP,and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics,including tissue overgrowth,cell-invasive behavior,abnormal cell polarity,and cell adhesion defects.dNKAP knockdown causes both R-loop accumulation and DNA damage,indicating the disruption of genome integrity.Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase(JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations.Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues.Furthermore,JNK signaling is essential for dNKAP depletion-mediated cell invasion.Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAP knockdown and oncogenic Ras,Notch,or Yki mutations show synergies in driving tumorigenesis,further supporting the tumor-suppressive role of dNKAP.In summary,this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

关 键 词：Drosophila wing imaginal disc dNKAP genome instability tumorigenic growth 

分 类 号：Q78[生物学—分子生物学]