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IQGAP3 interacts with Rad17 to recruit the Mre11-Rad50-Nbs1 complex and contributes to radioresistance in lung cancer.
Cancer Letters ( IF 9.7 ) Pub Date : 2020-09-04 , DOI: 10.1016/j.canlet.2020.08.042
Yulan Zeng 1 , Xiaohua Jie 1 , Bian Wu 1 , Gang Wu 1 , Li Liu 1 , Shuangbing Xu 1
Affiliation  

IQ motif containing GTPase-activating protein 3 (IQGAP3) has been implicated in diverse cellular processes, including neuronal morphogenesis, cell proliferation and motility, and epithelial-mesenchymal transition. However, its role in cancer radioresistance is completely unknown. Here, we report that IQGAP3 is overproduced in lung cancer patients and correlates with poor clinical outcomes. Functionally, we demonstrate that depletion of IQGAP3 impairs oncogenesis and overcomes radioresistance in lung cancer in vitro and in vivo. Mechanistically, we uncover that IQGAP3 interacts with Rad17 and controls its expression to activate the ATM/Chk2 and ATR/Chk1 signaling pathways by recruiting the Mre11-Rad50-Nbs1 (MRN) complex in response to DNA damage. Moreover, Rad17 is identified as the major downstream effector that mediates the functions of IQGAP3 in lung cancer. Clinically, IQGAP3 overexpression positively correlates with Rad17 upregulation in human lung cancer tissues. Collectively, these data support key role for IQGAP3 in promoting lung cancer radioresistance by interacting with Rad17 and suggest that targeting IQGAP3 may be an attractive strategy for lung cancer radiotherapy.



中文翻译:

IQGAP3与Rad17相互作用以募集Mre11-Rad50-Nbs1复合物,并有助于肺癌的放射抗性。

包含GTPase激活蛋白3(IQGAP3)的IQ基序已涉及多种细胞过程,包括神经元形态发生,细胞增殖和运动以及上皮-间质转化。但是,它在癌症抗辐射性中的作用是完全未知的。在这里,我们报道IQGAP3在肺癌患者中过量产生,并且与不良的临床结果相关。在功能上,我们证明了IQGAP3的耗竭会损害肿瘤发生并在体外体内克服肺癌的抗辐射性。从机制上讲,我们发现IQGAP3与Rad17相互作用并控制其表达以通过招募Mre11-Rad50-Nbs1(MRN)复合体来响应DNA损伤,从而激活ATM / Chk2和ATR / Chk1信号通路。此外,Rad17被认为是在肺癌中介导IQGAP3功能的主要下游效应物。在临床上,IQGAP3过表达与人肺癌组织中Rad17的上调正相关。总体而言,这些数据支持IQGAP3通过与Rad17相互作用来促进肺癌放射抵抗的关键作用,并表明靶向IQGAP3可能是肺癌放射治疗的一种有吸引力的策略。

更新日期:2020-09-05
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