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

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

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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 changes in cell proliferation in distinct cell populations.Activation of the Notch and Janus kinase/signal transducer and activator of transcription(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.

Drosophila wing imaginal discdNKAPgenome instabilitytumorigenic growth

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

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Division of Human Reproduction and Developmental Genetics,Women's Hospital,Zhejiang University School of Medicine,Hangzhou 310058,China

Institute of Genetics,Zhejiang University School of Medicine,Hangzhou 310058,China

Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases,Women's Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China

State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China

Cancer Center,Zhejiang University,Hangzhou 310058,China

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National Natural Science Foundation of China

31970668

2023

10.1093/jmcb/mjad078

分子细胞生物学报(英文版)
中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD
影响因子：0.595
ISSN：1673-520X
年,卷(期)：2023.(12)
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