WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit

作     者：Xiaomeng Gao Jieqiong You Yanling Gong Meng Yuan Haiying Zhu Liang Fang Hong Zhu Meidan Ying Qiaojun He Bo Yang Ji Cao 

作者机构：Institute of Pharmacology and ToxicologyZhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in MedicineZhejiang UniversityHangzhou 310058China Department of BiologySouthern University of Science and TechnologyShenzhen 518055China Cancer Center of Zhejiang UniversityHangzhou 310058China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第3期

页      面：1225-1239页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床] 

基　　金：supported by grants from Zhejiang Provincial Natural Science Foundation(No.Y18H310001 to Ji Cao,China) the National Natural Science Foundation of China(No.81872885 to Ji Cao No.81625024 to Bo Yang) the Talent Project of Zhejiang Association for Science and Technology(No.2018YCGC002 to Ji Cao,China)。 

主　　题：Transcription factors c-Myc WSB1 Ubiquitinationproteasome pathway β-Catenin destruction complex Feedback loop Tumorigenesis Cancer treatment 

摘      要：The dysregulation of transcription factors is widely associated with tumorigenesis.As the most well-defined transcription factor in multiple types of cancer,c-Myc can transform cells by transactivating various downstream genes.Given that there is no effective way to directly inhibit c-Myc,c-Myc targeting strategies hold great potential for cancer therapy.In this study,we found that WSB1,which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples,is a direct target gene of c-Myc,and can positively regulate c-Myc expression,which forms a feedforward circuit promoting cancer development.RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted cMyc expression through theβ-catenin pathway.Mechanistically,WSB1 affectedβ-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptorβ-TRCP recruitment,which inhibited the ubiquitination ofβ-catenin and transactivated c-Myc.Of interest,the effect of WSB1 on c-Myc was independent of its E3 ligase activity.Moreover,overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression.Thus,our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role,highlighting a potential c-Myc intervention strategy in cancer treatment.