An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness

Lei Liu, Tianyu Tao, Shihua Liu, Xia Yang, Xuwei Chen, Jiaer Liang, Ruohui Hong, Wenting Wang, Yi Yang, Xiaoyi Li, Youhong Zhang, Quanfeng Li, Shujun Liang, Haocheng Yu, Yun Wu, Xinyu Guo, Yan Lai, Xiaofan Ding, Hongyu Guan, Jueheng Wu, Xun Zhu, Jie Yuan, Jun Li, Shicheng Su, Mengfeng Li, Xiuyu Cai (), Junchao Cai () and Han Tian ()
Additional contact information
Lei Liu: Sun Yat-Sen University
Tianyu Tao: Sun Yat-Sen University
Shihua Liu: Sun Yat-sen University Cancer Center
Xia Yang: Sun Yat-Sen University
Xuwei Chen: Sun Yat-Sen University
Jiaer Liang: Sun Yat-Sen University
Ruohui Hong: Sun Yat-Sen University
Wenting Wang: Sun Yat-Sen University
Yi Yang: Sun Yat-Sen University
Xiaoyi Li: Sun Yat-Sen University
Youhong Zhang: Southern Medical University
Quanfeng Li: Southern Medical University
Shujun Liang: Sun Yat-Sen University
Haocheng Yu: Guangzhou No. 2 High School
Yun Wu: Sun Yat-Sen University
Xinyu Guo: Southern Medical University
Yan Lai: First Affiliated Hospital of Guangzhou Medical University
Xiaofan Ding: The Chinese University of Hong Kong
Hongyu Guan: The First Affiliated Hospital of Sun Yat-sen University
Jueheng Wu: Sun Yat-Sen University
Xun Zhu: Sun Yat-Sen University
Jie Yuan: Sun Yat-Sen University
Jun Li: Sun Yat-Sen University
Shicheng Su: Sun Yat-sen University
Mengfeng Li: Sun Yat-Sen University
Xiuyu Cai: Sun Yat-sen University Cancer Center
Junchao Cai: Sun Yat-sen University Zhongshan School of Medicine
Han Tian: Sun Yat-Sen University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.

Date: 2021
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DOI: 10.1038/s41467-021-22971-x

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