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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DOI：
10.1093/jmcb/mjad078
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发表时间：
2024-05-06
影响因子：
5.5
通讯作者：
Ge，Wanzhong
中科院分区：
文献类型：
--
作者：
Guo，Ting;Miao，Chen;Ge，Wanzhong
在人类癌症中发现了NF-κ B激活蛋白（NKAP）家族基因的突变或表达失调。NKAP家族基因突变如何促进肿瘤的发生和进展仍有待确定。在此，我们描述了果蝇中NKAP的同源物dNKAP的特征，并在果蝇上皮肿瘤模型中发现dNKAP功能受损导致基因组不稳定和致瘤性生长。dNKAP敲低的翅盘表现出致瘤性特征，包括组织过度生长、细胞侵袭行为、异常细胞极性和细胞粘附缺陷。dNKAP敲低导致R环积累和DNA损伤，表明基因组完整性的破坏。进一步的分析表明，dNKAP敲低诱导c-Jun N-末端激酶（JNK）依赖性凋亡，并导致不同细胞群的异常细胞增殖。Notch和JAK/STAT信号通路的激活有助于dNKAP敲低组织的致瘤性生长。此外，JNK信号传导对于dNKP耗竭介导的细胞侵袭是必需的。对dNKAP敲除组织的转录组分析证实了参与促进肿瘤发生的信号通路的错误调节，并揭示了代谢通路的异常调节。dNKAP敲除和致癌Ras、Notch或Yki突变在驱动肿瘤发生中显示出协同作用，进一步支持了dNKAP的肿瘤抑制作用。总之，本研究表明dNKAP通过防止果蝇上皮细胞基因组不稳定而发挥肿瘤抑制作用，从而为人类NKAP家族基因在肿瘤发生和发展中的作用提供了新的见解。
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, theDrosophilahomolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in aDrosophilaepithelial tumor model.dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell-invasive behavior, abnormal cell polarity, and cell adhesion defects.dNKAPknockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed thatdNKAPknockdown 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 ofdNKAP-knockdown tissues. Furthermore, JNK signaling is essential fordNKAPdepletion-mediated cell invasion. Transcriptome analysis ofdNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways.dNKAPknockdown 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 inDrosophilaepithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.