Original articles
Xiaomeng Gao, Jieqiong You, Yanling Gong, Meng Yuan, Haiying Zhu, Liang Fang, Hong Zhu, Meidan Ying, Qiaojun He, Bo Yang, Ji Cao. WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1225-1239

WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit
Xiaomeng Gaoa, Jieqiong Youa, Yanling Gonga, Meng Yuana,b, Haiying Zhua, Liang Fangc, Hong Zhua,d, Meidan Yinga,d, Qiaojun Hea,b,d, Bo Yanga,b, Ji Caoa,b,d
a. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;
b. The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China;
c. Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China;
d. Cancer Center of Zhejiang University, Hangzhou 310058, China
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 c-Myc expression through the β-catenin pathway. Mechanistically, WSB1 affected β-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-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.
Key words:    Transcription factors    c-Myc    WSB1    Ubiquitination-proteasome pathway    β-Catenin destruction complex    Feedback loop    Tumorigenesis    Cancer treatment   
Received: 2021-06-28     Revised: 2021-09-13
DOI: 10.1016/j.apsb.2021.10.021
Funds: This work was 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), and the Talent Project of Zhejiang Association for Science and Technology (No.2018YCGC002 to Ji Cao, China).
Corresponding author: Ji Cao,E-mai:caoji88@zju.edu.cn     Email:caoji88@zju.edu.cn
Author description:
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Xiaomeng Gao
Jieqiong You
Yanling Gong
Meng Yuan
Haiying Zhu
Liang Fang
Hong Zhu
Meidan Ying
Qiaojun He
Bo Yang
Ji Cao

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