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

Gao，Xiaomeng1; You，Jieqiong1; Gong，Yanling1; Yuan，Meng1,2; Zhu，Haiying1; Fang，Liang3; Zhu，Hong1,4; Ying，Meidan1,4; He，Qiaojun1,2,4; Yang，Bo1,2; Cao，Ji1,2,4

2021

10.1016/j.apsb.2021.10.021

Acta Pharmaceutica Sinica B   影响因子和分区

2211-3835

2211-3843

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.

c-Myc Cancer treatment Feedback loop Transcription factors Tumorigenesis Ubiquitination-proteasome pathway WSB1 β-catenin destruction complex

SCI

英语

其他

Zhejiang Provincial Natural Science Foundation[Y18H310001] ; National Natural Science Foundation of China[81872885,81625024]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000779784100004

INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES

2-s2.0-85120654746

Scopus

1.Institute of Pharmacology and Toxicology,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China
2.The Innovation Institute for Artificial Intelligence in Medicine,Zhejiang University,Hangzhou,310058,China
3.Department of Biology,Southern University of Science and Technology,Shenzhen,518055,China
4.Cancer Center of Zhejiang University,Hangzhou,310058,China

Gao，Xiaomeng,You，Jieqiong,Gong，Yanling,et al. WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit[J]. Acta Pharmaceutica Sinica B,2021,12(3).

Gao，Xiaomeng.,You，Jieqiong.,Gong，Yanling.,Yuan，Meng.,Zhu，Haiying.,...&Cao，Ji.(2021).WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit.Acta Pharmaceutica Sinica B,12(3).

Gao，Xiaomeng,et al."WSB1 regulates c-Myc expression through β-catenin signaling and forms a feedforward circuit".Acta Pharmaceutica Sinica B 12.3(2021).